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Cited by 56Pluripotent Stem Cells ResearchDevelopmental Biology and Gene RegulationNeurogenesis and neuroplasticity mechanisms

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Cellular plasticity in reprogramming, rejuvenation and tumorigenesis: a pioneer TF perspective

Open access
Huyghe, Aurélia, Trajkova, Aneta, Lavial, Fabrice·2024·Trends in Cell Biology
DOI 10.1016/j.tcb.2023.07.013
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Abstract

The multistep process of in vivo reprogramming, mediated by the transcription factors (TFs) Oct4, Sox2, Klf4, and c-Myc (OSKM), holds great promise for the development of rejuvenating and regenerative strategies. However, most of the approaches developed so far are accompanied by a persistent risk of tumorigenicity. Here, we review the groundbreaking effects of in vivo reprogramming with a particular focus on rejuvenation and regeneration. We discuss how the activity of pioneer TFs generates cellular plasticity that may be critical for inducing not only reprogramming and regeneration, but also cancer initiation. Finally, we highlight how a better understanding of the uncoupled control of cellular identity, plasticity, and aging during reprogramming might pave the way to the development of rejuvenating/regenerating strategies in a nontumorigenic manner.

Checked 2026-11-10 · 2 references not checked yet

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that OSKM-mediated in vivo reprogramming can rejuvenate and improve regeneration but carries a persistent tumorigenic risk, with pioneer transcription factors generating cellular plasticity that underlies both beneficial and malignant outcomes. It proposes that uncoupling cellular identity, plasticity, and aging could enable nontumorigenic reprogramming-based strategies.

Key findings

  • Partial/cyclic OSKM can reverse aging features: OSKMLN in aged (60–90 years) versus young (25–35 years) fibroblasts/endothelial cells induced rapid, persistent amelioration of aging hallmarks and reversal of cellular age; cyclic OSKM (2 days per week) erased epigenetic signs of aging and improved aging hallmarks, though age reduction was constrained to kidney and skin.
  • OSKM effects are dose-, duration-, and cell-type-dependent: short OSKM exposure (6–12 days) in adult cardiomyocytes reprogrammed them toward a fetal state and improved heart repair; 6 days caused moderate reversible cardiac remodeling, while 21 days triggered epithelial-like neoplasms, and one OSKM allele led to cardiac neoplasms after 7 weeks. Low OSKM expression led to teratomas, whereas high OSKM triggered malignant tumors.
  • Tumorigenic risk accompanies in vivo reprogramming: full reprogramming forms teratomas, and premature termination after ~7 days of OSKM produced malignant tumors in various organs, whereas dysplasia after short exposure (~2 days) was often reversed. Excluding c-Myc avoided cancerous eye lesions after prolonged expression.
  • Pioneer TFs generate cellular plasticity through promiscuous chromatin binding: Myod1 binds neuronal genes and Ascl1 binds myogenic genes; Atoh8 controls cellular plasticity; early intermediates can be highly prone to iPSC generation without significant loss of MEF identity, and rejuvenation may occur before identity changes in some settings.

Methods

  • Review article; no primary experimental design, sample, or statistical analysis is reported. It synthesizes published studies on in vivo OSKM reprogramming, partial reprogramming, rejuvenation/regeneration, tumorigenesis, and pioneer TF activity.
  • Main analysis is a narrative synthesis, supported by conceptual figures and a table of pioneer TF functions across development, regeneration, and tumorigenesis.

Limitations

  • Stated: in vivo reprogramming studies are not numerous and most findings still rely on in vitro work; the molecular bases of cell type- and organ-specific sensitivity remain imperfectly understood; results are difficult to compare because the reprogramming cocktail and duration of exposure often differ.
  • Stated: functional and physiological effects of rejuvenation need systematic assessment; partial restoration of youthful gene expression is limited and may not correlate with functional reversion; lineage-tracing tools and more human-cell studies are needed.
  • Evident: as a review, it does not provide new experimental data, and several mechanistic claims are synthesized from referenced studies rather than directly tested here.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.tcb.2023.07.013

Cites

105 of 107 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 111 cited sources checked · 0 supported · 0 flagged

  • Premisecitation
    § Pluripotent reprogramming is a stepwise process

    Oct4, Sox2, and Klf4 belong to the family of pioneer transcription factors, able to interact with and remodel the nucleosome to open silent chromatin.

    “Oct4, Sox2, and Klf4 belong to the family of 'pioneer' TFs, a specific class of molecules able to interact with, and remodel, the nucleosome to open silent chromatin [16].”
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  • Premisecitation
    § A tumorigenic risk is associated with in vivo reprogramming

    Comparison of the roadmaps of reprogramming and transformation at the single cell level in mouse embryonic fibroblasts demonstrated the existence of an early shared epigenetic program induced by OSKM and oncogenic K-Ras/c-Myc.

    “Comparison of the roadmaps of reprogramming and transformation at the single cell level in mouse embryonic fibroblasts (MEFs) demonstrated the existence of an early shared epigenetic program induced by OSKM and oncogenic K-Ras/c-Myc (Figure 1) [6].”
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  • Premisecitation
    § Glossary

    Partial reprogramming in myofibers promoted tissue regeneration in a chemically induced tibialis anterior muscle degeneration model.

    “Similarly, partial reprogramming in myofibers promoted tissue regeneration in a chemically induced tibialis anterior muscle degeneration model.”
    Quote in the paperNot a substantial claim
  • Premisecitation
    § Pluripotent reprogramming is a stepwise process

    Partial reprogramming approaches restored vision.

    “These approaches led to groundbreaking effects both in vitro and in vivo, including rejuvenation [8][9][10][11], improvement of regenerative abilities in various organs [9,12,13], and restoration of vision [14].”
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  • Premisecitation
    § Glossary

    Many epigenetic marks remodeled during early reprogramming are also dysregulated during aging, including post-translational DNA methylation, histone modifications, and chromatin remodeling.

    “Many of the epigenetic marks that are remodeled during early reprogramming are also dysregulated during the aging process, including post-translational DNA methylation, modifications of histones, and chromatin remodeling [23].”
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    Premisenone given
    § Glossary

    OSKM improved recovery from toxin-mediated pancreas and muscle injury and reduced scar tissue formation following cutaneous wounds.

    “OSKM also improved recovery from toxin-mediated pancreas and muscle injury and also reduced scar tissue formation following cutaneous wounds.”
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    Premisecitation
    § Pluripotent reprogramming is a stepwise process

    Reprogramming is a stepwise process marked by the emergence of cellular intermediate states, with progressive gain of cellular plasticity and loss of cellular identity followed by activation of the pluripotent network.

    “Reprogramming is a stepwise process marked by the emergence of cellular intermediate states, presenting a progressive gain of cellular plasticity (see Glossary) and loss of cellular identity followed by the activation of the pluripotent network [5,6].”
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    Premisecitation
    § Glossary

    Senescence promotes in vivo reprogramming via paracrine secretion of a variety of molecules, including IL-6.

    “Senescence also promotes in vivo reprogramming via the paracrine secretion of a variety of molecules, including IL-6 [21].”
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    Premisecitation
    § Glossary

    OSK expression in mouse retinal ganglion cells restored youthful DNA methylation and transcriptomic patterns and reversed vision loss in both a glaucoma model and aged mice.

    “Additionally, OSK expression in mouse retinal ganglion cells was found to restore youthful DNA methylation/transcriptomic patterns and to reverse vision loss in both a model of glaucoma and aged mice [14].”
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    Premisenone given
    § Glossary

    Adult mammalian cardiomyocytes are poorly proliferative and have low regenerative capability.

    “Adult mammalian cardiomyocytes (CMs) are poorly proliferative and have low regenerative capability.”
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    Premisecitation
    § Glossary

    Various epigenetic clocks were developed to estimate age based on the level of methylation of a restricted number of CpG sites in the genome.

    “In line with this, various epigenetic clocks were developed to estimate age based on the level of methylation of a restricted number of CpG sites in the genome [24][25][26].”
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    Premisecitation
    § Reprogramming in vivo triggers rejuvenation and improves regeneration

    Reprogramming to pluripotency and generation of iPSCs is achievable in vivo, indicating that the microenvironment is not sufficient to constrain OSKM action.

    “Reprogramming to pluripotency and generation of iPSCs is achievable in vivo, indicating that the microenvironment is not sufficient to constrain OSKM action [3].”
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    Premisecitation
    § Glossary

    Partial and cyclic reprogramming with OSKM 2 days per week led to erasure of epigenetic signs of aging and amelioration of various aging hallmarks in pathological and normal aging.

    “In addition, pioneer works revealed that a regimen of partial and cyclic reprogramming (mice were exposed to OSKM 2 days per week) led to the erasure of epigenetic signs of aging and to the amelioration of various aging hallmarks in the context of not only pathological, but also normal aging [9,11,28].”
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    Premisecitation
    § Glossary

    Cyclic OSKM expression induces rejuvenation in the central nervous system and restored adult hippocampal neuron migration in the dentate gyrus of old mice, associated with partial improvement of cognitive functions.

    “Cyclic OSKM expression also induces rejuvenation in the central nervous system.It restored adult hippocampal neuron migration in the dentate gyrus of old mice, associated with partial improvement of cognitive functions [30].”
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    Premisenone given
    § A tumorigenic risk is associated with in vivo reprogramming

    An acute effect of OSKM is formation of dysplastic lesions in multiple tissues, but dysplasia is often reversed following short exposure to OSKM of about 2 days.

    “An acute effect of OSKM is the formation of dysplastic lesions in multiple tissues, but dysplasia is often reversed following short exposure to OSKM (~2 days).”
    Quote in the paperSubstantial claim

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    Premisenone given
    § Glossary

    OSKM action is dependent on the developmental stage of cardiomyocytes; it can sustain an immature proliferative state in neonatal cardiomyocytes while allowing acquisition of a mitosis-competent state in adult cardiomyocytes.

    “OSKM action is dependent on the developmental stage of CMs.It can sustain an immature proliferative state in neonatal CMs, while allowing the acquisition of a mitosis-competent state in adult CMs.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Glossary

    Repeated induction of double-strand breaks led to erosion of the epigenetic landscape, partial loss of cellular identity, senescence, and advancement of the DNA methylation clock.

    “However, the repeated induction of DSBs led to the erosion of the epigenetic landscape, partial loss of cellular identity, senescence, and advancement of DNA methylation clock [24].”
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  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given
    § Glossary

    The parameters of OSKM exposure, expression level and duration, required to achieve beneficial effects are cell type and/or organ specific.

    “However, the parameters of OSKM exposure (expression level and duration) required to achieve beneficial effects are cell type and/or organ specific.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Reprogramming in vivo triggers rejuvenation and improves regeneration

    OSKM ubiquitous expression triggers formation of differentiated teratomas in various organs, revealing that multiple cell types are capable of reprogramming with different kinetics.

    “In detail, OSKM ubiquitous expression triggers the formation of differentiated teratomas in various organs (pancreas, kidney, intestine, adipose tissue, liver, intracranial, stomach, and heart), revealing that multiple cell types are capable of reprogramming with different kinetics [3,10].”
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    Premisenone given
    § A tumorigenic risk is associated with in vivo reprogramming

    The full reprogramming process ultimately leads to formation of teratomas, but development of these benign tumors reflects acquisition of a multilineage differentiation potential.

    “As mentioned previously, the full process ultimately leads to the formation of teratomas, but the development of these benign tumors simply reflects the acquisition of a multilineage differentiation potential.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § Outstanding questions

    Pioneer TFs subsequently trigger nucleosome remodeling and induce different transcriptional programs to dictate embryonic lineage segregation and ensure lineage fidelity.

    “Pioneer TFs subsequently trigger nucleosome remodeling and induce different transcriptional programs to dictate embryonic lineage segregation and ensure lineage fidelity[42].”
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    Premisecitation
    § Outstanding questions

    During normal development, developmental signals drive the expression of pioneer TFs by specific enhancers.

    “During normal development, developmental signals drive the expression of pioneer TFs by specific enhancers.”
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    Premisecitation
    § Outstanding questions

    LINE-1 expression is high in pre-implantation embryos, in which it regulates transcription and developmental potency.

    “Meanwhile, LINE-1 expression is high in pre-implantation embryos, in which it regulates transcription and developmental potency [67].”
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    Premisecitation
    § Reprogramming generates cellular plasticity

    The trajectories of reprogramming are dependent on the cell type of origin and on the cocktail of factors.

    “Of note, the trajectories of reprogramming are dependent on the cell type of origin and on the cocktail of factors [37,38].”
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    Premisecitation
    § Outstanding questions

    Myt1l converts the pro-myogenic factor Myod1 into a pro-neuronal factor by inhibiting the muscle program and exploiting Myod1 promiscuous binding to neuronal genes.

    “Myt1l converts the pro-myogenic factor Myod1 into a pro-neuronal factor by inhibiting the muscle program and exploiting Myod1 promiscuous binding to neuronal genes [47].”
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    Premisecitation
    § Pioneer TF activity in regeneration and cancer initiation

    In the lung, TP53 promotes lineage infidelity and its genetic inactivation stalls cells in a mixed state, indicating that loss of this tumor suppressor can be directly responsible for persistence of lineage infidelity.

    “In the lung, TP53 promotes lineage infidelity and its genetic inactivation stalls the cells in this mixed state, indicating that the loss of this tumor suppressor can be directly responsible for the persistence of lineage infidelity [52].”
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    Premisecitation
    § Trends in Cell Biology

    OSK expression in inducible changes to the epigenome fibroblasts restored age-associated mRNA changes and epigenetic age without impacting cellular identity.

    “OSK expression in inducible changes to the epigenome (ICE) fibroblasts restored age-associated mRNA changes and epigenetic age without impacting cellular identity [23].”
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    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    Ascl1 and Myod1 are two pioneer basic helix-loop-helix transcription factors that are sequence related but drive transdifferentiation of mouse embryonic fibroblasts into neural and muscular cells, respectively.

    “As another example, Ascl1 and Myod1 are two pioneer basic helix-loop-helix (bHLH) TFs that are sequence related but drive the transdifferentiation of MEFs into neural and muscular cells, respectively [17] (Figure 2B).”
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    Premisereasoning
    § Pioneer TF activity in regeneration and cancer initiation

    Numerous embryonic pioneer transcription factors are induced in adult lineages in response to stress and/or during cancer formation, highlighting how embryonic programs might have been co-opted during evolution as stress-response options.

    “Numerous embryonic pioneer TFs are induced in adult lineages in response to stress and/or during cancer formation, highlighting how embryonic programs might have been co-opted during evolution as stress-response options (Table 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given
    § Concluding remarks

    Pioneer TF activity is directly related to their ability to reprogram, regenerate, and potentially poise the cells for oncogenic transformation.

    “Pioneer TF activity is directly related to their ability to reprogram, regenerate, and potentially poise the cells for oncogenic transformation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Interpretationnone given
    § Outstanding questions

    During the early phase of reprogramming, the epigenetic marks are remodeled and cellular intermediates gain in cellular plasticity.

    “During the early phase of reprogramming, the epigenetic marks are remodeled and cellular intermediates gain in cellular plasticity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    Myod1 binds promiscuously to neuronal genes and Ascl1 to myogenic ones.

    “Moreover, and in line with the generation of cellular plasticity by pioneer TFs, the pro-myogenic factor Myod1 was found to bind promiscuously to neuronal genes and the pro-neuronal factor Ascl1 to myogenic ones [47].”
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    Interpretationcitation
    § Trends in Cell Biology

    If reprogramming is separated into three phases, initiation, maturation, and stabilization, rejuvenation could be pushed to the maturation phase, where the complete pluripotency program is attained.

    “By contrast, work in human fibroblasts showed that, if reprogramming were to be separated in three phases (initiation, maturation, and stabilization), rejuvenation could be pushed to the maturation phase, where the complete pluripotency program is attained [57].”
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    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    Distinct changes in fate specification were due to strong differences in DNA-binding affinity of Ascl1 and Myod1 and to their respective interaction with cofactors.

    “These distinct changes in fate specification were found to be due to strong differences in the DNA-binding affinity of Ascl1 and Myod1 and to their respective interaction with cofactors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation
    § Reprogramming generates cellular plasticity

    Aberrant gene inductions initially reported in pioneer bulk RNA-sequencing analysis were considered to be disorganized gene expression.

    “Interestingly, aberrant gene inductions were initially reported in pioneer bulk RNA-sequencing analysis but considered to be disorganized gene expression [39].”
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    Premisecitation
    § Outstanding questions

    Depletion of LINE-1 RNA in dermal fibroblast cells from patients with different progeroid syndromes restores heterochromatin H3K9Me3/H3K27Me3 marks and reverses DNA methylation age in vitro.

    “Depletion of LINE-1 RNA in dermal fibroblast cells from patients with different progeroid syndromes was recently found to restore heterochromatin H3K9Me3/H3K27Me3 marks and reverse DNA methylation age in vitro [68].”
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    Premisecitation
    § Uncoupling cellular identity, plasticity, and aging during reprogramming

    Fibroblast identity repression occurs by distinct mechanisms depending on the reprogramming factor used, Ascl1, MyoD1, FoxA2, Sox2, or Oct4, and no general principle emerged, highlighting that different entry points exist to erase cell identity.

    “Fibroblast identity repression was found to occur by distinct mechanisms depending on the reprogramming factor used (Ascl1, MyoD1, FoxA2, Sox2, or Oct4) and no general principle emerged, highlighting that different entry points exist to erase cell identity [55].”
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    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    Nucleosomes impair DNA binding of transcription factors, but a specific class of embryonic pioneer transcription factors interact with and remodel the nucleosome to open silent chromatin.

    “Nucleosomes impair DNA binding of TFs, but a specific class of embryonic 'pioneer' TFs interact with, and remodel, the nucleosome to open silent chromatin, as reviewed elsewhere [42].”
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    Interpretationcitation
    § Trends in Cell Biology

    The effect of OSKMLN on the epigenetic clock of human fibroblasts and endothelial cells occurs before epigenetic changes of cellular identity, indicating that rejuvenation may be achievable while preserving cellular identity.

    “The effect of OSKMLN on the epigenetic clock of human fibroblasts and endothelial cells was also described to occur before the epigenetic changes of cellular identity, indicating that rejuvenation may be achievable while preserving cellular identity [8].”
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    Premisecitation
    § Outstanding questions

    The termination of pluripotent reprogramming (cyclic or by pulse) in this time window contributes to rejuvenation and regeneration.

    “The termination of pluripotent reprogramming (cyclic or by pulse) in this time window contributes to rejuvenation and regeneration[9,11].”
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    Premisecitation
    § Uncoupling cellular identity, plasticity, and aging during reprogramming

    A special relationship between the germ layer of the cell of origin and the transcription factor was evidenced, and the mesodermal factor Myod1 was found to repress fibroblast identity most potently.

    “A special relationship between the germ layer of the cell of origin and the TF was evidenced, and the mesodermal factor Myod1 was found to repress fibroblast identity most potently.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning
    § Outstanding questions

    Reprogramming can trigger not only rejuvenation but also cancer development.

    “Reprogramming can trigger not only rejuvenation but also cancer development.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given
    § Outstanding questions

    The dosage of OSKM controls the final epigenetic landscape of reprogramming.

    “The dosage of OSKM controls the final epigenetic landscape of reprogramming.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    During early steps of reprogramming, OSK redistribute c-Myc on the mouse embryonic fibroblast genome, which may divert it from its tumorigenic action.

    “During the early steps of reprogramming, OSK were found to redistribute c-Myc on the MEF genome, which may divert it from its tumorigenic action [45].”
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    Interpretationreasoning
    § Outstanding questions

    Reprogramming triggers various outcomes, including rejuvenation, regeneration, and cancer.

    “reprogramming triggers various outcomes, including rejuvenation, regeneration, and cancer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § Outstanding questions

    Nanog was reported to confer a youthful phenotype to senescent myoblasts and to improve molecular features of skeletal muscle in a mouse model of premature aging.

    “Moreover, Nanog was also reported to confer a youthful phenotype to senescent myoblasts and to improve molecular features of skeletal muscle in a mouse model of premature aging [64].”
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    Interpretationreasoning
    § Outstanding questions

    After the point of no return, the outcome of prolonged reprogramming and oncogenic transformation is engaged.

    “After this point, the outcome of prolonged reprogramming and oncogenic transformation is engaged.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Interpretationnone given
    § Outstanding questions

    The effects of reprogramming are due, at least partly, to epigenetic modifications that depend on OSKM level and duration of expression.

    “These effects are due, at least partly, to epigenetic modifications that depend on OSKM level and duration of expression.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning
    § Pioneer TF activity in regeneration and cancer initiation

    Pioneer transcription factor activity influences both regeneration and tumorigenesis.

    “These findings highlight how pioneer TF activity influences both regeneration and tumorigenesis.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation
    § A tumorigenic risk is associated with in vivo reprogramming

    Low OSKM expression led to teratoma formation, whereas high levels triggered generation of malignant tumors.

    “Low OSKM expression led to teratoma formation, whereas high levels triggered the generation of malignant tumors [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisenone given
    § Pioneer TF activity in regeneration and cancer initiation

    During wound repair, activity of stress-responsive enhancers decreases and the Klf5/Sox9 balance is restored.

    “However, during wound repair, the activity of those 'stress-responsive' enhancers decreases and the Klf5/Sox9 balance is restored.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation
    § Reprogramming generates cellular plasticity

    Alternative routes appear mainly absent from chemical-mediated reprogramming, indicating that use of pioneer transcription factors might be responsible for aberrant acquisition of cellular plasticity.

    “Nonetheless, these alternative routes appear mainly absent from chemical-mediated reprogramming, indicating that the use of pioneer TFs (see next section) might be responsible for such aberrant acquisition of cellular plasticity [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning
    § A tumorigenic risk is associated with in vivo reprogramming

    DNA methylation changes were partial, indicating that abnormal growth of unsuccessfully reprogrammed cells can lead to tumor formation in which a hybrid epigenetic landscape has been stabilized.

    “Similarly, DNA methylation changes were partial, indicating that the abnormal growth of unsuccessfully reprogrammed cells can lead to tumor formation in which a hybrid epigenetic landscape has been stabilized (Figure 1).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation
    § A tumorigenic risk is associated with in vivo reprogramming

    Short OSKM exposure of 6 days led to moderate signs of reversible cardiac remodeling, while prolonged time of 21 days triggered development of epithelial-like neoplasms.

    “Short OSKM exposure (6 days) led to moderate signs of reversible cardiac remodeling, while prolonged time (21 days) triggered the development of epithelial-like neoplasms.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given
    § Concluding remarks

    Somatic cells acquire a hybrid unstable epigenetic landscape that is initially reversible.

    “As depicted in Figure 1, we posit that somatic cells acquire a hybrid unstable epigenetic landscape that is initially reversible.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § Outstanding questions

    The pioneer TFs OSK trigger widespread reconfiguration of chromatin and redistribute on the chromatin c-Myc and MEF cofactors, such as Runx1, Cebpa/b, and Fra1.

    “The pioneer TFs OSK trigger widespread reconfiguration of chromatin and redistribute on the chromatin c-Myc and mouse embryonic fibroblast (MEF) cofactors, such as Runx1, Cebpa/b, and Fra1[18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation
    § A tumorigenic risk is associated with in vivo reprogramming

    Tumors in the pancreas harbor gene signatures related to germ cell tumors, in accordance with a rejuvenating role of OSKM.

    “Tumors in the pancreas harbor gene signatures related to germ cell tumors, in accordance with a 'rejuvenating' role of OSKM [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationcitation
    § Uncoupling cellular identity, plasticity, and aging during reprogramming

    An optimal, cell type-specific level of reprogramming factors exists, which is sufficient for reprogramming and may also minimize the risk of failure and/or tumorigenicity.

    “It indicates that an optimal, cell type-specific level of reprogramming factors exists, which is sufficient for reprogramming and that may also minimize the risk of failure and/or tumorigenicity [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning
    § Reprogramming generates cellular plasticity

    The action of pioneer transcription factors is not exclusively deterministic toward a specific cell fate; pioneer transcription factors also generate cellular plasticity and windows of opportunity for somatic cells to engage into alternative paths.

    “Collectively, these studies show that the action of pioneer TFs is not exclusively deterministic toward a specific cell fate.Pioneer TFs also generate cellular plasticity and windows of opportunity for somatic cells to engage into alternative paths.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation
    § Pioneer TF activity during reprogramming and transdifferentiation

    NeuroD1 during direct conversion of mouse microglia into neurons involves transcriptional repressors; NeuroD1 initially binds closed bivalent chromatin regions to induce neuronal gene expression, and among its primary targets, transcriptional repressors Scrt1 and Meis2 are induced to silence the microglial program.

    “Furthermore, dissecting the action of the pioneer TF NeuroD1 during the direct conversion of mouse microglia into neurons also involves transcriptional repressors.NeuroD1 initially binds to closed bivalent chromatin regions to induce neuronal gene expression.Among NeurodD1 primary targets, the transcriptional repressors Scrt1 and Meis2 are induced to silence the microglial program [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisenone given
    § Pioneer TF activity in regeneration and cancer initiation

    Acinar-to-ductal metaplasia facilitates pancreas regeneration and is resolved by redifferentiation.

    “This transient process, termed acinar-to-ductal metaplasia (ADM), facilitates pancreas regeneration and is resolved by redifferentiation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Premisecitation
    § Outstanding questions

    During tumorigenesis, activation of novel high stress enhancers by the oncogenic insult stabilizes lineage infidelity events.

    “During tumorigenesis, activation of novel high stress enhancers by the oncogenic insult stabilizes lineage infidelity events[69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Premisecitation
    § Outstanding questions

    Pioneer TF expression is transiently activated via stress and/or injury enhancers during regeneration, leading to mixed cellular identity.

    “Pioneer TF expression is transiently activated via stress and/or injury enhancers during regeneration, leading to mixed cellular identity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation
    § Outstanding questions

    These transient lineage infidelity events contribute to repair and are rapidly resolved by redifferentiation.

    “These transient lineage infidelity events contribute to repair and are rapidly resolved by redifferentiation[54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

59 of 59

  • The paper relies on this without support.

    Studies of reprogramming in vivo are not numerous and most findings still rely on in vitro work.

    “First, the studies of reprogramming in vivo are not numerous and most findings still rely on in vitro work.”

  • The paper relies on this without support.

    The partial restoration of a youthful gene expression pattern is limited and may not significantly correlate with the functional reversion of an aging phenotype.

    “The partial restoration of a youthful gene expression pattern is limited and may not significantly correlate with the functional reversion of an aging phenotype.”
2 of 2

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Metadata

Authors
Huyghe, A., Trajkova, A., & Lavial, F.
Affiliations
Lyon 1 Université (FR)
Corresponding author
Lavial, Fabrice
ORCID
Venue
Trends in Cell Biology
Publisher
Elsevier BV
Published
2024-03
Volume
34
Issue
3
Pages
255-267
ISSN
0962-8924 (ISSN-L)
DOI
10.1016/j.tcb.2023.07.013
OpenAlex
W4386226359
Cited by
56
References
108
Citations by year
2026: 19 · 2025: 20 · 2024: 15
FWCI
1.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Cell Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
Funders
  • Agence Nationale de la Recherche (ANR-10-LABX-0061)
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation pour la Recherche Médicale
  • Fondation ARC pour la Recherche sur le Cancer
  • Ligue Contre le Cancer
  • Centre National de la Recherche Scientifique
  • Institut National Du Cancer
  • Fondation Bettencourt Schueller
  • Centre Léon Bérard
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
cellular plasticity, in vivo reprogramming, OSKM transcription factors, rejuvenation, tissue regeneration, carcinogenesis, tumor initiation, aging, cell identity, pioneer transcription factors
MeSH terms
Cell Plasticity, Cell Transformation, Neoplastic, Humans, Rejuvenation, Transcription Factors, Octamer Transcription Factor-3, SOXB1 Transcription Factors, Induced Pluripotent Stem Cells, Carcinogenesis, Cellular Reprogramming

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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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