The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index; 3 of the 39 sources its claims cite were checked for support.
In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche
Open accessAbstract
Short-term, systemic expression of the Yamanaka reprogramming factors ( Oct-3/4 , Sox2 , Klf4 and c-Myc [OSKM]) has been shown to rejuvenate aging cells and promote tissue regeneration in vivo. However, the mechanisms by which OSKM promotes tissue regeneration are unknown. In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice. In contrast, expressing OSKM directly in SCs does not improve muscle regeneration. Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4 . This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence. Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.
Overview
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TL;DR
Myofiber-specific, short-term OSKM induction in mice activates satellite cells and accelerates muscle regeneration by inducing p21 and repressing the myofiber-secreted niche factor Wnt4; SC-specific OSKM induction does not improve regeneration. The effect is aging-independent and can be recapitulated by cyclic Wnt4 knockdown.
Key findings
- Myofiber-specific OSKM induction before injury accelerated regeneration: Cre+ muscles had more eMHC+ myofibers at day 3, more Pax7+ cells, larger regenerated myofibers, more Pax7+MyoD+ myoblasts, and higher hindlimb grip strength at day 6; OSKM induction after injury did not accelerate regeneration.
- OSKM in myofibers promoted SC activation/proliferation: Cre+ muscles had a 3-fold higher percentage of Pax7+BrdU+ cells; single Cre+ myofibers had 2-fold more Pax7+ cells and 3-fold more activated MyoD+ SCs, with quiescent MyoD− SCs decreased by half. Self-renewal was maintained after serial injuries.
- SC-specific OSKM induction did not activate/proliferate SCs or improve regeneration; in cultured myoblasts, OSKM inhibited MyoD and miR-133a.
- Mechanistically, Wnt4 was the only niche-related gene downregulated >2-fold; p21 was upregulated, p21 overexpression increased p21 60-fold and downregulated Wnt4 3-fold, ChIP showed 3-fold enrichment at the Wnt4 TATA-proximal region, and p21 inhibited a Wnt4 reporter 2-fold. Cyclic CasRx Wnt4 knockdown (gRNA1: 85% in vitro, 65% in vivo) recapitulated SC activation and regeneration. In 15-month-old mice, Cre+ muscles had 1.8-fold more Pax7+ cells, 2.8-fold more MyoD+ SCs, and 3-fold more BrdU+ SCs.
Methods
- Generated myofiber-specific Acta1-Cre/4Fhet and SC-specific Pax7creER/4Fhet inducible OSKM mouse models; used young (6 weeks–4 months) and aging (12–15 months) mice, both male and female. Doxycycline was given in drinking water (1 mg/ml), often cyclically (2 days on/5 days off), with cardiotoxin injury, BrdU labeling, and tamoxifen for Pax7creER induction.
- Readouts included RNA-seq of EDL/SOL muscles after 2.5 or 8.5 days Dox (DESeq2, WGCNA, GO/GSEA), qPCR, immunostaining/H&E, single myofiber isolation and culture, western blot, ChIP, luciferase assays, and AAV9-CasRx-mediated Wnt4 knockdown.
- Statistical analysis used two-tailed unpaired Student’s t-test with p<0.05; RNA-seq OSKM/niche comparisons used n=2 biological samples, while many histology experiments used n=4–6 mice.
Limitations
- Stated: the authors cannot exclude that other cell types (macrophages, endothelial cells, fibroblasts) or ECM/exosome-mediated indirect effects contribute to SC activation; two possible explanations for maintained SC self-renewal (homeostatic mechanism vs. temporary niche modification) were not distinguished.
- Stated: timing is important—post-injury OSKM did not accelerate regeneration—and systemic vs. myofiber-specific OSKM differ in induction level and p21 induction in SCs.
- Evident: findings are in mice only; key RNA-seq comparisons for OSKM/niche genes used n=2 biological samples; and although both male and female mice were used, sex-specific effects were not analyzed.
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Claims the paper makes
115 Own result · 35 Own interpretation · 24 Not checked yet · 4 No basis given · 2 Supported
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In the paper
“Besides amelioration of cellular aging hallmarks, reprogramming factors promote tissue regeneration in aged mice8,10.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Supportedcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
The Discussion (p. 1730) states that short-term induction of the reprogramming factors OSKM improved regeneration of the pancreas and muscle after injury in physiologically aged mice. This directly supports the claim that reprogramming factors promote tissue regeneration in aged mice. (LLM, conf=0.94)
- Supportedcites [10] Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). source
The ‘OSK stimulates axon regeneration’ section reports robust axon regeneration after OSK treatment in 12-month-old mice. This supports the claim for regeneration in the eye’s nervous tissue of older mice. (LLM, conf=0.90)
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In the paper
“Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
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In the paper
“In contrast, expressing OSKM directly in SCs does not improve muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
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In the paper
“In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
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In the paper
“Mechanistically, expressing OSKM in myofibers regulates the expression of genes important for the SC microenvironment, including upregulation of p21, which in turn downregulates Wnt4.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In this work, we focus on a specific tissue and demonstrate that local expression of OSKM, specifically in myofibers, induces the activation of muscle stem cells or satellite cells (SCs), which accelerates muscle regeneration in young mice.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
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“Activated genes were enriched in pathways related to cytoskeleton organization (Supplementary Fig. 2b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“We first sought to confirm OSKM expression, and indeed measured higher levels of OSKM in Cre+ EDL muscles compared with Cre− EDL muscles (Fig. 1c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“As with the PCA analysis, the gene expression level induced or repressed by OSKM was more pronounced in EDL muscles than in SOL muscles (Supplementary Fig. 2a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“In addition, the expression of Oct4, Sox2, and c-Myc was 4-fold higher in Cre+ EDL muscles compared with Cre+ SOL muscles (baseline expression of these genes was comparable between Cre− EDL and Cre− SOL muscles) (Fig. 1c, d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“In contrast, 181 and 202 genes were upregulated and downregulated, respectively, only in the 8.5-day treatment group (Fig. 1h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“In addition, 2.5 and 8.5 days of Dox treatment induced a similar Euclidean distance between the Cre+ and Cre− samples, consistent with the PCA analysis (Fig. 1e, f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“Each of these three modules contained genes repressed or activated by OSKM induction in both EDL and SOL muscles (Supplementary Fig. 2a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“Interestingly, more genes were differentially expressed following 2.5 days of OSKM induction than seen following 8.5 days of treatment (Fig. 1g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“In contrast, SC-specific OSKM induction does not improve muscle regeneration in young mice.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
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“Gene set enrichment analysis (GSEA) showed that 2.5 and 8.5 days of treatment affected the same genetic pathways (Supplementary Fig. 3a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“First, levels of OSKM upregulation were comparable between 2.5 and 8.5 days of Dox administration (Fig. 1c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“Immunostaining verified the expression of Sox2 and GFP in extensor digitorum longus (EDL) muscles of Acta1-Cre+/4Fhet mice but not in Acta1-Cre−/4Fhet mice after introduction of Dox (1 mg/ml) in their drinking water for 2.5 days (Supplementary Fig. 1).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“A total of 1142 genes were upregulated and 697 genes were downregulated only in the 2.5-day treatment group (Fig. 1h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“The repressed genes were enriched for pathways related to metabolism and muscle differentiation (Supplementary Fig. 2b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“The 2.5-day and 8.5-day treatment regimens shared 876 upregulated and 578 downregulated genes (Fig. 1h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“Co-staining of Pax7 and BrdU did not show a difference in the percentage of Pax7+BrdU+ cells, as all SCs entered into the cell cycle at the early stage of regeneration (Fig. 2e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“In contrast, the number of Pax7+MyoD− SCs was comparable in Cre− and Cre+ samples (Fig. 2i), indicating Cre+ samples had an expansion of myoblasts without changing the SCs number.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“The percentage of SCs-derived myocytes (MyoD+Pax7−) was comparable between Cre+ and Cre− muscles (Fig. 3d, f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Cre+ samples had more Pax7+MyoD+ myoblasts than Cre− samples (Fig. 2i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“Compared to mature eMHC− myofibers, eMHC+ immature myofibers had a smaller myofiber size (Fig. 2g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“As a consequence, Cre+ muscles had more Pax7+ cells than Cre− muscles (Fig. 3d, e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“These data show that OSKM induction after muscle injury could not accelerate muscle regeneration, reinforcing the benefits of preinjury induction of OSKM.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“Whereas Cre+ and Cre− hind limbs had similarly low grip strength 1 day post CTX injection, Cre+ muscles had higher grip strength than Cre− muscles 6 days post CTX treatment (Fig. 2j), indicating that Cre+ muscles restored their function faster than Cre− muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“Immunostaining confirmed the specific expression of Oct4 in nuclei of myofibers but not in Pax7+ (the SCs marker) cells after 2 days of Dox treatment (Fig. 2b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“Cre+ muscles had a lower percentage of eMHC+ regenerating myofibers compared to Cre− muscles (Fig. 2g), indicating a higher percentage of mature regenerating myofibers in Cre+ muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“Co-staining these muscles for BrdU and Pax7 showed that Cre+ muscles had a 3-fold higher percentage of Pax7+BrdU+ cells than Cre− muscles, indicating that myofiber-specific expression of OSKM promoted the proliferation of SCs (Fig. 3b, c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Cre+ muscles had more eMHC+ myofibers compared to Cre− muscles (Fig. 2d), indicating an earlier regenerative process in Cre+ muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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“In addition, immunostaining showed that there are no eMHC+ myofibers in Cre− and Cre+ muscles before an injury (Supplementary Fig. 5b), indicating that the activated SCs did not spontaneously contribute to myofibers of Cre+ muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“The number of cell clusters was significantly higher in Cre+ myofibers than Cre− myofibers (Fig. 3k, l).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Fibrosis was similarly low in Cre+ and Cre− muscles (Fig. 4k), and myofiber sizes were comparable between Cre+ and Cre− muscles (Fig. 4l).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“Co-staining of MyoD and Pax7 showed that Cre+ muscles had more Pax7+ cells compared to Cre− muscles 14 days post CTX injection (Fig. 4b, c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“Additionally, all Pax7+ cells expressed MyoD in both Cre− and Cre+ myofibers (Fig. 3k).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“The percentage of Pax7+MyoD− SCs, which are capable of self-renewal was comparable between Cre+ and Cre− muscles (Fig. 4b, c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“As expected, we found SC doublets, indicative of SC proliferation, only in Cre+ myofibers (Supplementary Fig. 5d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Cre+ muscles had a lower percentage of eMHC+ regenerating myofibers compared to Cre− muscles (Fig. 4d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“The number of Pax7+ cells was comparable between Cre+ and Cre− muscles (Fig. 5f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“The number of Pax7+MyoD+ myoblast per cluster was higher in Cre+ myofibers (Fig. 3k, m), excluding the possibility that the activated SCs exited the cell cycle for premature differentiation.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“At 7 days after the last CTX injury (day 21), there was no difference in the number of Pax7+ cells between Cre+ and Cre− muscles (Fig. 5b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“Moreover, the percentage of activated (MyoD+) SCs was 3-fold higher in Cre+ myofibers than Cre− myofibers (Fig. 3h, j).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Cre+ myofibers were associated with 2-fold more Pax7+ cells than Cre− myofibers (Fig. 3h, i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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“Mallory’s trichrome staining showed that the Cre+ muscles had less fibrosis compared to Cre− muscles (Fig. 4e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“OSKM inhibited the expression of MyoD and miR-133a (Supplementary Fig. 7b), which is consistent with the finding that Oct4 represses the expression of MyoD18.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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“Real-time PCR using whole muscle lysates confirmed that OSKM was induced immediately after Dox treatment (Supplementary Fig. 6a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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“Co-staining of BrdU and Pax7 showed that Cre+ muscles had a 3-fold higher percentage of BrdU+ SCs than Cre− muscles (Supplementary Fig. 8e, f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“The expression level of OSKM in skeletal muscles of systemic 4F mice was 5–10 times lower than that in Acta-Cre/4Fhet mice which were administrated with doxycycline in water (Supplementary Fig. 9e, f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“In addition, Cre+ muscles had more SCs than Cre− muscles (Supplementary Fig. 8j, k).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“The percentage of Pax7+MyoD−BrdU+ SCs was also similar in Cre+ and Cre− muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“Cre+ muscles had fewer eMHC+ myofibers compared with Cre− muscles (Supplementary Fig. 8 h, i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“We found that the percentage of activated (MyoD+) SCs was increased by 1.7-fold (Supplementary Fig. 9b, c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“Six days post-injury, no differences in the morphology or size of regenerated myofibers were observed between Cre+ and Cre− muscles (Supplementary Fig. 6 h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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“In addition, the number of myoblasts in regenerated muscles was comparable between Cre+ and Cre− muscles (Supplementary Fig. 6i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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In the paper
“We did not observe a significant difference in the number of Pax7+ cells as seen in Acta-Cre/4Fhet mice (Supplementary Fig. 9b, d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“Isolated myofibers were cultured for 2 days in Dox (1 µg/ml), which induced the expression of OSKM in Cre+ myofibers (Fig. 6d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“RNA-seq analysis revealed that 2.5 and 8.5 days of Dox treatment affected the expression of 13 niche-related genes in Cre+ muscles (Fig. 6a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“Consistent with this, in vivo levels of p53 and p21 protein were increased in Cre+ muscles isolated from Acta1-Cre/4Fhet mice after 2.5 days of Dox treatment (Fig. 6f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“h Enrichments of the TATA-proximal region of the Wnt4 promoter by 3xFLAG-p21 as determined by ChIP assay using an antibody against FLAG.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“In mouse keratinocytes, p21 inhibits Wnt4 expression by binding to the TATA-proximal region of the Wnt4 promoter in association with E2F transcription factor 1 (E2F-1)24, and levels of p21 expression were negatively correlated with Wnt4 expression in our RNA-seq analysis (Fig. 6b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“The ChIP assay showed a 3-fold enrichment of the TATA-proximal region in muscles with p21 overexpression (Fig. 6h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“rWnt4 significantly decreased the expression of MyoD and abolished the upregulation of active Yap in Pax7+ cells from Cre+ myofibers 8 h after treatment (Supplementary Fig. 10d–f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“More Pax7+ cells per cluster were found in Cre+ myofibers compared to Cre− myofibers 48 h after treatment, which was abrogated by rWnt4 treatment (Supplementary Fig. 10g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“we verified that Wnt4 expression was decreased by 65% in left TA muscles compared to right TA muscles following Dox treatment, and returned to control levels following Dox withdrawal (Fig. 7b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“Our results showed that all three gRNAs could efficiently diminish the mCherry signal (Supplementary Fig. 11a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“the percentage of Pax7+MyoD+ active Yap+ cells was 3-fold higher in Cre+ myofibers than in Cre− myofibers (Supplementary Fig. 10b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“rWnt4 did not change the expression of active Yap and MyoD in Pax7+ cells from Cre− myofibers”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“myofibers in KD muscles were larger than those observed in control, with more myofibers that were 30–40 µm and less that were 10–20 µm in diameter (Fig. 7i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“p21 inhibited the PWnt4−Pmin-Luc reporter by 2-fold (Fig. 6i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“Whereas p21 was unable to affect the control reporter (Pmin-Luc), which lacks the TATA-proximal region”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“KD muscles had more Pax7+MyoD+ myoblasts than control muscles (Fig. 7h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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In the paper
“KD muscles had 2-fold more Pax7+ cells and 3-fold more activated (MyoD+) SCs than control muscles (Fig. 7e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“levels of active Yap were higher in Pax7+ cells from Cre+ myofibers than in Pax7+ cells from Cre− myofibers (Supplementary Fig. 10a, b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“the number of Pax7+MyoD− SCs was comparable in control and KD samples (Fig. 2i)”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“KD muscles had 1-fold less eMHC+ myofibers compared with control muscles (Fig. 7g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“myofibers in KD muscles were larger than those observed in control, with more myofibers that were 30–40 µm and less that were 10–20 µm in diameter (Fig. 7i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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In the paper
“KD muscles had 2-fold more Pax7+ cells and 3-fold more activated (MyoD+) SCs than control muscles (Fig. 7e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“In contrast, there was no enrichment of the TATA-proximal region in control muscles (Fig. 6h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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“we verified that Wnt4 expression was decreased by 65% in left TA muscles compared to right TA muscles following Dox treatment, and returned to control levels following Dox withdrawal (Fig. 7b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“gRNA1 decreased the expression of Wnt4 by 85%, and both gRNA2 and gRNA3 decreased the expression of Wnt4 by around 75% compared with mock gRNA (Supplementary Fig. 11b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“left muscles (with AAV-gRNA1-CasRx, KD) had a 3-fold higher percentage of Pax7+BrdU+cells than right (with AAV-CasRx, control) (Fig. 7d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“rWnt4 significantly decreased the expression of MyoD and abolished the upregulation of active Yap in Pax7+ cells from Cre+ myofibers 8 h after treatment (Supplementary Fig. 10d–f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“myofibers in KD muscles were larger than those observed in control, with more myofibers that were 30–40 µm and less that were 10–20 µm in diameter (Fig. 7i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“gRNA1 decreased the expression of Wnt4 by 85%, and both gRNA2 and gRNA3 decreased the expression of Wnt4 by around 75% compared with mock gRNA (Supplementary Fig. 11b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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“More Pax7+ cells per cluster were found in Cre+ myofibers compared to Cre− myofibers 48 h after treatment, which was abrogated by rWnt4 treatment (Supplementary Fig. 10g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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“As injury is a strong signal to trigger SC proliferation, the effect of OSKM on SC activation and proliferation was negligible after injury, and thus post-injury induction of OSKM did not accelerate muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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“In contrast, systemic OSKM induction did not change the number of Pax7+ cells in naturally aging mice after 3 weeks of cyclic induction of OSKM.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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“As injury is a strong signal to trigger SC proliferation, the effect of OSKM on SC activation and proliferation was negligible after injury, and thus post-injury induction of OSKM did not accelerate muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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“In addition, SC-specific OSKM induction did not change the quantity of SCs or myoblasts and thus no difference in muscle regeneration was observed.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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“In addition, SC-specific OSKM induction did not change the quantity of SCs or myoblasts and thus no difference in muscle regeneration was observed.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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In the paper
“In our model, the myofiber-specific OSKM induction did not change the number and state of SCs after multiple muscle injuries.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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In the paper
“However, reprogramming in vivo induces tumor development5–7.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Not checked yetcites [5] Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 502, 340–345 (2013). source
- Not checked yetcites [6] Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677 (2014). source
- Not checked yetcites [7] Shibata, H. et al. In vivo reprogramming drives Kras-induced cancer development. Nat. Commun. 9, 2081 (2018). source
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“Thus, short-term induction of the Yamanaka factors in myofibers may promote tissue regeneration by modifying the stem cell niche.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
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“This is critical because Wnt4 is secreted by myofibers to maintain SC quiescence.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Abstract
What the sources say
- Not checked yetcites [23] Eliazer, S. et al. Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654–665.e4 (2019). source
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In the paper
“Our data shows that myofiber-specific OSKM induction accelerates muscle regeneration through downregulating the myofiber-secreted niche factor, Wnt4, to induce the activation and proliferation of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
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“We have shown that partial reprogramming promotes skeletal muscle regeneration in 12-month-old mice8, but these studies were performed by expressing OSKM systemically (i.e., in all cell types)8.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Not checked yetcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
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In the paper
“These results indicate that OSKM was more strongly induced in fast-twitch muscles than in slow-twitch muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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“Whereas Cre+ and Cre− hind limbs had similarly low grip strength 1 day post CTX injection, Cre+ muscles had higher grip strength than Cre− muscles 6 days post CTX treatment (Fig. 2j), indicating that Cre+ muscles restored their function faster than Cre− muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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In the paper
“All the Pax7+ cells were Td−, indicating that Pax7+ cells were not derived from myofibers (Supplementary Fig. 5c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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In the paper
“In addition, immunostaining showed that there are no eMHC+ myofibers in Cre− and Cre+ muscles before an injury (Supplementary Fig. 5b), indicating that the activated SCs did not spontaneously contribute to myofibers of Cre+ muscles.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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In the paper
“These data show that OSKM induction after muscle injury could not accelerate muscle regeneration, reinforcing the benefits of preinjury induction of OSKM.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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In the paper
“These results suggest that partial reprogramming of myofibers accelerated muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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In the paper
“The number of Pax7+MyoD+ myoblast per cluster was higher in Cre+ myofibers (Fig. 3k, m), excluding the possibility that the activated SCs exited the cell cycle for premature differentiation.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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In the paper
“These results further confirm that myofiber-specific OSKM induction accelerated muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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In the paper
“These results show that the SC pool was maintained after OSKM induction.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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In the paper
“Together, these data prove that myofiber-specific OSKM induction did not change the self-renewal capacity of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
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“The induction of p21 could negatively regulate the G1 to S progression of satellite cells19.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
What the sources say
- Not checked yetcites [19] McCroskery, S., Thomas, M., Maxwell, L., Sharma, M. & Kambadur, R. Myostatin negatively regulates satellite cell activation and self-renewal. J. Cell Biol. 162, 1135–1147 (2003). source
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In the paper
“The number of Pax7+ cells, as well as the percentages of MyoD+ and BrdU+ SCs were all comparable between Cre+ and Cre− muscles (Supplementary Fig. 6e–g), indicating that SC-specific OSKM induction did not lead to the activation and proliferation of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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In the paper
“Our results provide an additional explanation for the improved muscle regeneration in systemic 4F mice besides SC rejuvenation.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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“We previously showed that systemic OSKM induction could promote muscle regeneration in 12-month-old systemic 4F mice8.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
What the sources say
- Not checked yetcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
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In the paper
“Based on these observations, we conclude that the cyclic induction of OSKM in young SCs did not improve muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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“It is known that OSKM induction activates the p53–p21 pathway25.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [25] Hong, H. et al. Suppression of induced pluripotent stem cell generation by the p53-p21 pathway. Nature 460, 1132–1135 (2009). source
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“Wnt family member 4 (Wnt4) is a recently identified paracrine factor that is secreted from myofibers23.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [23] Eliazer, S. et al. Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654–665.e4 (2019). source
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In the paper
“OSKM in myofibers inhibits Wnt4 expression through p21”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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In the paper
“Specifically, expressing OSKM in myofibers induced p53–p21 signaling, which subsequently inhibited Wnt4 transcription.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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In the paper
“Together, these results indicate that cyclic Wnt4 knockdown recapitulated OSKM induction to induce SC activation and myoblasts expansion to promote muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
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In the paper
“Our work demonstrates that partial reprogramming via OSKM can remodel a stem cell niche to induce stem cell activation and proliferation and accelerate muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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In the paper
“These results prove that OSKM induction downregulated the expression of Wnt4 through p21.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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In the paper
“These results indicate that the repression of Wnt4 was responsible for OSKM induction-induced SCs activation and proliferation by activating MyoD and Yap.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Wnt4 diminishes OSKM-induced SC changes
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In the paper
“SCs activation is required for muscle regeneration, but the activation kinetics is delayed in aged SCs30.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [30] Kimmel J. C., Hwang A. B., Scaramozza A., Marshall W. F., Brack A. S. Aging induces aberrant state transition kinetics in murine muscle stem cells. Development 147, dev183855 (2020). source
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In the paper
“The downregulation of Wnt4 contributed to the activation of MyoD and Yap in SCs, resulting in their proliferation.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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In the paper
“Systemic OSKM induction has been shown to mitigate the decline of Pax7+ cells in progeria mice after 6 weeks of cyclic induction of OSKM8.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our results suggest that modifying the stem cell niche could be a definitive intervention to boost young tissue regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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- Rests on an assumption: The intrinsic regulatory machinery is efficient in young SCs.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, diminishment of the SC pool is not observed when SCs-SC niche molecular interactions are interrupted in muscles lacking Wnt4, N-, and M-cadherins or syndecan-323,39,40.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [23] Eliazer, S. et al. Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654–665.e4 (2019). source
- Not checked yetcites [39] Goel, A. J., Rieder, M. K., Arnold, H. H., Radice, G. L. & Krauss, R. S. Niche cadherins control the quiescence-to-activation transition in muscle stem cells. Cell Rep. 21, 2236–2250 (2017). source
- Not checked yetcites [40] Pisconti, A. et al. Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration. Skelet. Muscle 6, 34 (2016). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The intrinsic regulatory machinery is efficient in young SCs, therefore, further improvement of SC quality is limited.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
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- Rests on an assumption: The intrinsic regulatory machinery is efficient in young SCs.
In the paper
“Interestingly, the effect of cyclic Wnt4 knockdown on muscle regeneration is similar to permanent Wnt4 knockdown23.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [23] Eliazer, S. et al. Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654–665.e4 (2019). source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“We identified Wnt4 as a downstream target of OSKM and found that cyclic Wnt4 knockdown could facilitate SC activation and muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We identified Wnt4 as a downstream target of OSKM and found that cyclic Wnt4 knockdown could facilitate SC activation and muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 16
- It may state two separate claims as one. 35
- The quote only partly states this claim. 2
Every source the paper cites for this claim was checked and supports it.
In the paper
“Reprogramming factors have been shown to promote axon regeneration through intrinsic rejuvenation of retinal ganglion cells10.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Supportedcites [10] Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). source
In “OSK stimulates axon regeneration” (page not provided), the paper reports that expressing Oct4, Sox2 and Klf4 in retinal ganglion cells promotes axon regeneration, while expression in amacrine cells does not. “Regeneration requires DNA demethylation” (page not provided) links this effect to reprogramming within the ganglion cells, supporting the paraphrase of intrinsic rejuvenation. (LLM, conf=0.92)
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Principal component analysis (PCA) of the RNA-seq data revealed a clear separation between Cre+ and Cre− samples, and the separation distance was wider in EDL muscles than in SOL muscles (Fig. 1e), consistent with the levels of OSKM induction.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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In the paper
“In SOL muscles, however, Oct4, Sox2, and c-Myc were induced, but the expression of Klf4 was similar between Cre+ and Cre− SOL muscles (Fig. 1d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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In the paper
“Furthermore, DE genes resulting from 2.5 or 8.5 days of treatment had similar distribution patterns when visualized using volcano plots (Fig. 1g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
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In the paper
“Eleven modules were identified, but only three were enriched for GO terms associated with biological processes (Supplementary Fig. 2a, b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, Cre+ samples had more Pax7+ cells than Cre− samples (Fig. 2e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
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In the paper
“Co-staining for Pax7 and MyoD showed that Cre+ muscles had a higher percentage of activated (MyoD+) SCs and a lower percentage of quiescent (MyoD−) SCs than Cre− muscles (Fig. 3d, f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“H&E staining did not reveal any morphological differences between Cre+ and Cre− muscle sections and the myofibers in Cre− and Cre+ muscles lacked central nuclei (Supplementary Fig. 5a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The GO biological process term most enriched in these upregulated genes was related to cytoskeleton organization, whereas downregulated genes were related to oxidative phosphorylation (Fig. 1h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“OSKM expression was induced in the TA muscle following 2 days of Dox treatment, with OSKM levels returning back to control levels following 5 days of withdrawal (Fig. 2a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“These 202 downregulated genes were enriched in GO biological process terms related to cellular response to stimulus (Supplementary Fig. 3b), whereas the 181 upregulated genes were not enriched for a specific GO biological process term.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistently, regenerated myofibers in Cre+ muscles were larger than those observed in Cre− muscles, with more myofibers that were 30–40 µm and fewer that were 10–20 µm in diameter (Fig. 2h).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“At 30 days post-injury, the number of Pax7+ cells and the percentage of Pax7+MyoD− SCs were comparable between Cre+ and Cre− muscles (Fig. 4h, i).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Muscle structure was restored and there were no eMHC+ myofibers in Cre+ and Cre− muscles (Fig. 4j).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Fibrosis was similarly low in Cre+ and Cre− muscles (Fig. 4k), and myofiber sizes were comparable between Cre+ and Cre− muscles (Fig. 4l).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The percentage of eMHC+ regenerating myofibers and myofiber sizes were comparable between Cre+ and Cre− muscles (Fig. 5c, d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, regenerated myofibers in Cre+ muscles were larger than those observed in Cre− muscle, with more myofibers that were 50–60 µm in diameter (Fig. 4f).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers does not change SC self-renewal
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Conversely, the percentage of quiescent (MyoD−) SCs was decreased by half in Cre+ myofibers compared to Cre− myofibers, and there was no difference in the percentage of MyoD+Pax7− cells (Fig. 3h, j).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, p21 was induced in the SCs of systemic 4F muscles but not in the SCs of Acta-Cre/4Fhet mice (Supplementary Fig. 9 g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
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In the paper
“Cre+ muscles had 1.8-fold more Pax7+ cells and 2.8-fold more activated (MyoD+) SCs than Cre− muscles (Supplementary Fig. 8b-d).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, myofibers in Cre+ muscles were larger than those observed in Cre− muscle, with more myofibers that were 30–40 µm and fewer myofibers that were 10–20 µm in diameter (Supplementary Fig. 8 l).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The number of Pax7+ cells, as well as the percentages of MyoD+ and BrdU+ SCs were all comparable between Cre+ and Cre− muscles (Supplementary Fig. 6e–g), indicating that SC-specific OSKM induction did not lead to the activation and proliferation of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
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In the paper
“Expression of four of these genes (Itga7, Sdc4, Wnt2b, and Wnt4) was altered on average over two-fold, and among these, Wnt4 was the only one that was downregulated (Fig. 6a).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
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In the paper
“Electroporation of the CAG-3xFLAG-p21 plasmid increased p21 expression 60-fold, and downregulated Wnt4 levels 3-fold, compared with the control plasmid (CAG-Td) (Fig. 6g).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The expression of p21 and Wnt4 were significantly upregulated and downregulated, respectively, in Cre+ myofibers compared to Cre− myofibers (Fig. 6e).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Levels of p21 and Wnt4 expression were upregulated and downregulated in Cre+ muscles, respectively, following Dox treatment, and returned to control levels (i.e., levels seen in Cre− samples) following Dox withdrawal (Fig. 6c).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both myofiber-specific and systemic OSKM induction increased the activation of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our lab showed that partial reprogramming by short-term expression of reprogramming factors ameliorated aging hallmarks without tumor formation8, opening a possible application of this approach in vivo.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Not checked yetcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The regenerative capacity of SCs is influenced by both intrinsic modulators and the extrinsic microenvironment13–15.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Not checked yetcites [13] Blau, H. M., Cosgrove, B. D. & Ho, A. T. The central role of muscle stem cells in regenerative failure with aging. Nat. Med. 21, 854–862 (2015). source
- Not checked yetcites [14] Sousa-Victor, P. et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature 506, 316–321 (2014). source
- Not checked yetcites [15] Brack, A. S. & Munoz-Canoves, P. The ins and outs of muscle stem cell aging. Skelet. Muscle 6, 1 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that fast-twitch muscles are a more appropriate model for evaluating the effects of OSKM on muscle regenerative capacity.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > RNA-seq analysis of myofiber-specific OSKM induction mice
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Muscle regeneration is primarily mediated by muscle stem cells or satellite cells (SCs), which reside in a characteristic niche located between the basal lamina and plasma membrane of myofibers12.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
What the sources say
- Not checked yetcites [12] Mauro, A. Satellite cell of skeletal muscle fibers. J. Biophys. Biochem. Cytol. 9, 493 (1961). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that partial reprogramming via OSKM can remodel the SC niche to induce SC activation and proliferation and accelerate muscle regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Introduction
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, the number of Pax7+MyoD− SCs was comparable in Cre− and Cre+ samples (Fig. 2i), indicating Cre+ samples had an expansion of myoblasts without changing the SCs number.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results suggest that partial reprogramming of myofibers induced the activation and proliferation of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these results prove that partial reprogramming of myofibers induced the activation and proliferation of SCs and the expansion of myoblasts.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers promotes SC proliferation
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“OSKM inhibited the expression of MyoD and miR-133a (Supplementary Fig. 7b), which is consistent with the finding that Oct4 represses the expression of MyoD18.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in SCs does not change muscle regeneration
What the sources say
- Not checked yetcites [18] Watanabe, S. et al. MyoD gene suppression by Oct4 is required for reprogramming in myoblasts to produce induced pluripotent stem cells. Stem Cells 29, 505–516 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results indicate that myofiber-specific OSKM induction promotes SC activation and proliferation and accelerates muscle regeneration independent of aging.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction promotes proliferation of SCs in aging mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In mouse keratinocytes, p21 inhibits Wnt4 expression by binding to the TATA-proximal region of the Wnt4 promoter in association with E2F transcription factor 1 (E2F-1)24, and levels of p21 expression were negatively correlated with Wnt4 expression in our RNA-seq analysis (Fig. 6b).”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [24] Devgan, V., Mammucari, C., Millar, S. E., Brisken, C. & Dotto, G. P. p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation. Genes Dev. 19, 1485–1495 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Integrin subunit alpha 7 (Itga7) is a laminin-binding protein that connects myofibers to the basal lamina to maintain sarcolemma integrity20.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [20] Mayer, U. et al. Absence of integrin alpha 7 causes a novel form of muscular dystrophy. Nat. Genet. 17, 318–323 (1997). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Loss of Wnt4 in myofibers induces the activation of SCs and accelerates muscle regeneration23.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [23] Eliazer, S. et al. Wnt4 from the niche controls the mechano-properties and quiescent state of muscle stem cells. Cell Stem Cell 25, 654–665.e4 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Syndecan-4 (Sdc4) is expressed in SCs and is required for SC activation21,22, but a role for Sdc4 in myofibers remains elusive.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM in myofibers inhibits Wnt4 expression through p21
What the sources say
- Not checked yetcites [21] Bentzinger, C. F. et al. Fibronectin regulates Wnt7a signaling and satellite cell expansion. Cell Stem Cell 12, 75–87 (2013). source
- Not checked yetcites [22] Cornelison, D. D. et al. Essential and separable roles for Syndecan-3 and Syndecan-4 in skeletal muscle development and regeneration. Genes Dev. 18, 2231–2236 (2004). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Deletion of collagen VI or laminin-α1 (ECM components) or myofiber-specific deletion of O-fucosyltransferase 1 gene (Pofut1) impairs the self-renewal of SCs36–38, leading to the shrinkage of the SC pool after multiple muscle injuries.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [36] Rayagiri, S. S. et al. Basal lamina remodeling at the skeletal muscle stem cell niche mediates stem cell self-renewal. Nat. Commun. 9, 1075 (2018). source
- Not checked yetcites [37] Urciuolo, A. et al. Collagen VI regulates satellite cell self-renewal and muscle regeneration. Nat. Commun. 4, 1964 (2013). source
- Not checked yetcites [38] Zygmunt D. A. et al. Deletion of Pofut1 in mouse skeletal Myofibers induces muscle aging-related phenotypes in cis and in trans. Mol. Cell. Biol. 37, e00426–16 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, our results suggest an aging-independent effect of reprogramming factors on muscle regeneration through remodeling of the extrinsic niche but not by regulating the intrinsic modulators of SCs.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The increase in activated SCs accelerated muscle regeneration, which may partly explain our previous observation that muscle regeneration was promoted in aging systemic 4F mice8.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [8] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, e1712 (2016). 1719-1733. source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: SC activation is required for muscle regeneration.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The aging process is much slower in WT mice compared to progeria mice and longer time may be required to observe the effect of OSKM on SC number in naturally aging mice.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Rests on an assumption: The aging process is much slower in WT mice compared to progeria mice.
In the paper
“Intrinsic modulators control SC-initiated postnatal myogenesis29.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [29] Dumont, N. A., Wang, Y. X. & Rudnicki, M. A. Intrinsic and extrinsic mechanisms regulating satellite cell function. Development 142, 1572–1581 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Self-renewal of SCs is maintained by the SC niche, including, but not limited to ECM components and myofibers34,35.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [34] Kuang, S., Gillespie, M. A. & Rudnicki, M. A. Niche regulation of muscle satellite cell self-renewal and differentiation. Cell Stem Cell 2, 22–31 (2008). source
- Not checked yetcites [35] Yin, H., Price, F. & Rudnicki, M. A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“OSKM induction triggers complex cellular changes1–3.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
What the sources say
- Not checked yetcites [1] Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). source
- Not checked yetcites [2] Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). source
- Not checked yetcites [3] Polo, J. M. et al. A molecular roadmap of reprogramming somatic cells into iPS cells. Cell 151, 1617–1632 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The identification of their effective downstream targets would restrict unwanted outcomes and benefit the development of new approaches to facilitate tissue regeneration.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Young mice lack aging-related decline, so any OSKM-induced improvement in muscle regeneration in them cannot be attributed to rejuvenation of aged cells.
“In addition, we chose young mice to investigate whether the improvement of regeneration can be achieved by OSKM induction regardless of its rejuvenating effect.”
The paper relies on this without support.
The aging process is much slower in WT mice compared to progeria mice.
“The aging process is much slower in WT mice compared to progeria mice and longer time may be required to observe the effect of OSKM on SC number in naturally aging mice.”
The paper relies on this without support.
The intrinsic regulatory machinery is efficient in young SCs.
“The intrinsic regulatory machinery is efficient in young SCs, therefore, further improvement of SC quality is limited.”
The paper relies on this without support.
SC activation is required for muscle regeneration.
“SCs activation is required for muscle regeneration, but the activation kinetics is delayed in aged SCs30.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“They showed increased MuSC activation and proliferation only when the factors are overexpressed before the injury (both in old and young mice) without affecting their self-renewal capability.”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [111]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“suggesting that manipulation of specific pathways may be critical to achieving rejuvenation 111”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [111]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“arguing that the rejuvenation effect on MuSCs is cell nonautonomous and induced by myofibers 111 .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [111]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“the specific overexpression of the factors in MuSCs did not improve muscle regeneration”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [111]
The cited source says what the claim attributes to it.
In the citing paper
“This increase in MuSC proliferation upon OKSM overexpression was induced via p53-p21 signaling, which inhibits Wnt4 and contributes to the activation of MyoD and YaP in MuSCs”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [111]
In the citing paper
“The beneficial effects of OSKM on muscle function may be not cell autonomous: indeed expression of OSKM in myofibres, but not in MuSCs, promotes regeneration of old muscles232.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [232]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > Cyclic Wnt4 knockdown facilitates muscle regeneration
“In contrast, the number of Pax7+MyoD− SCs was comparable in control and KD samples (Fig. 2i), indicating Cre+ samples had an expansion of myoblasts without changing the SCs number.”
§ In vivo partial reprogramming of myofibers promotes muscle regeneration by remodeling the stem cell niche > Results > OSKM induction in myofibers accelerates muscle regeneration
“In contrast, the number of Pax7+MyoD− SCs was comparable in Cre− and Cre+ samples (Fig. 2i), indicating Cre+ samples had an expansion of myoblasts without changing the SCs number.”
Citations
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Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., & Yamanaka, S. (2007) · Cell · doi:10.1016/j.cell.2007.11.019 · Cited by 20,221
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
SATELLITE CELL OF SKELETAL MUSCLE FIBERS
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The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation
Chen, J., Mandel, E. M., Thomson, J. M., Wu, Q., Callis, T. E., Hammond, S. M., Conlon, F. L., & Wang, D.-Z. (2005) · Nature Genetics · doi:10.1038/ng1725 · Cited by 2,807
Satellite Cells and the Muscle Stem Cell Niche
Yin, H., Price, F., & Rudnicki, M. A. (2013) · Physiological Reviews · doi:10.1152/physrev.00043.2011 · Cited by 2,166
CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing
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Suppression of induced pluripotent stem cell generation by the p53–p21 pathway
Hong, H., Takahashi, K., Ichisaka, T., Aoi, T., Kanagawa, O., Nakagawa, M., Okita, K., & Yamanaka, S. (2009) · Nature · doi:10.1038/nature08235 · Cited by 1,301
Cited by
Sorted by citations
Meta-hallmarks of aging and cancer
López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L., & Kroemer, G. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.001 · Cited by 529
Control of satellite cell function in muscle regeneration and its disruption in ageing
Sousa-Victor, P., García-Prat, L., & Muñoz-Cánoves, P. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00421-2 · Cited by 476
Ageing and rejuvenation of tissue stem cells and their niches
Brunet, A., Goodell, M. A., & Rando, T. A. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00510-w · Cited by 407
Browder, K. C., Reddy, P., Yamamoto, M., Haghani, A., Guillen, I. G., Sahu, S., Wang, C., Luque, Y., Prieto, J., Shi, L., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00183-2 · Cited by 253
Self-citationHuman organoids-on-chips for biomedical research and applications
Wang, H., Ning, X., Zhao, F. H., Zhao, H., & Li, D. (2024) · Theranostics · doi:10.7150/thno.90492 · Cited by 148
Metadata
- Authors
- Wang, C., Rabadan Ros, R., Martinez-Redondo, P., Ma, Z., Shi, L., Xue, Y., Guillen-Guillen, I., Huang, L., Hishida, T., Liao, H.-K., Nuñez Delicado, E., Rodriguez Esteban, C., Guillen-Garcia, P., Reddy, P., & Izpisua Belmonte, J. C.
- Affiliations
- Salk Institute for Biological Studies (US)
- ORCID
- Venue
- Nature Communications
- Published
- 2021-05-25
- Volume
- 12
- Issue
- 1
- Pages
- 3094-3094
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8149870
- OpenAlex
- W3165546848
- Cited by
- 119
- References
- 55
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 27 · 2023: 28 · 2022: 17 · 2021: 7
- FWCI
- 6.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- This work was supported by Asociación de Futbolistas Españoles (AFE), Fundacion Pedro Guillen, Universidad Católica San Antonio de Murcia (UCAM), The Glenn Foundation, The Moxie Foundation and CIRM
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- partial reprogramming, Yamanaka factors, OSKM, muscle regeneration, satellite cells, muscle stem cells, stem cell niche, muscle fibers, Wnt4, p21, stem cell quiescence, aging cells, local gene expression
- MeSH terms
- Kruppel-Like Factor 4, Animals, Cell Differentiation, Cells, Cultured, Female, Mice, Transgenic, Myofibrils, Regeneration, Gene Expression, Proto-Oncogene Proteins c-myc, Satellite Cells, Skeletal Muscle, Octamer Transcription Factor-3, Kruppel-Like Transcription Factors, Stem Cell Niche, SOXB1 Transcription Factors, Wnt4 Protein, Cellular Reprogramming
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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