Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner
Open accessAbstract
Key Points: Total body irradiation causes long-term bone marrow suppression by selectively inducing HSC senescence. The induction of HSC senescence is independent of telomere shortening and p16Ink4a and Arf.
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Written from the paper’s full text.
TL;DR
In mice, sublethal total body irradiation (6 Gy) causes long-term bone marrow suppression by selectively inducing hematopoietic stem cell premature senescence, marked by SA-β-gal activity and p16/Arf upregulation, without telomere shortening or increased apoptosis. This HSC senescence and residual BM injury occur independently of p16Ink4a and Arf.
Key findings
- Two months after 6 Gy TBI, peripheral blood counts and BM cell numbers had returned to normal, but LSK cells remained significantly lower, mainly due to reduced MPPs; HSC numbers were relatively normal, yet functional HSCs were reduced by 4- and 6-week CAFCs and showed reduced long-term donor engraftment and myeloid skewing after transplantation.
- TBI selectively increased SA-β-gal in HSCs/LT-HSCs: about 12% of HSCs and 17% of LSK cells were SA-β-gal+, and irradiated HSCs expressed ~18-fold higher p16 and ~14-fold higher Arf mRNA; no significant increase in apoptosis was found.
- SA-β-gal+ LSK cells had higher p16, diminished in vitro proliferation, and lower long-term engraftment than SA-β-gal– LSK cells; ROS production was >1.7-fold higher in HSCs (vs ~1.2–1.3-fold in HPCs/MPPs), with reduced quiescence and increased BrdU labeling, but no telomere shortening.
- p16 and/or Arf knockout did not protect HSCs: irradiated KO HSCs showed similar SA-β-gal+, CAFC reductions, and, for p16 KO, engraftment defects as WT; p15 mRNA increased >80-fold in irradiated p16/Arf KO HSCs versus <10-fold in WT.
Methods
- Mice used: C57BL/6J, CD45.1, p16−/−, Arf−/−, and p16Arf−/−; exposed to sublethal 6.0 Gy TBI in a 137Ce γ-irradiator at 2.4 Gy/min.
- BM populations were analyzed by flow cytometry; functional assays included CAFC, competitive repopulation, single-cell culture, and sorting of SA-β-gal+ versus SA-β-gal– LSK cells; qRT-PCR measured gene expression; ROS, apoptosis, cell cycle, and BrdU incorporation were assessed; telomere length was measured by flow-FISH and qPCR.
- Statistical analysis details are in supplemental Methods.
Limitations
- Stated: only a small fraction of HSCs became senescent after TBI, and SA-β-gal– LSK cells from irradiated mice were also abnormal, suggesting dynamic or heterogeneous senescence.
- Stated: competitive repopulation was not performed on irradiated Arf and p16-Arf KO BM cells because these cells have a higher propensity for malignant transformation; p15 as a possible p16 substitute was not tested because Cdkn2ab−/− mice were unavailable.
- Evident: findings are from a mouse model using a single sublethal 6 Gy dose and a 2-month post-TBI time point, so human relevance and other doses or time points are not established.
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- Findingown data§ Results
No significant changes in apoptosis were found in HSCs from mice 2 months after TBI.
“In contrast, no significant changes in apoptosis were found in HSCs from mice 2 months after TBI based on the results from the Annexin V staining assay (Figure 3B).”
Quote in the paperSubstantial claim - Findingown data§ Results
TBI did not significantly change the frequencies and numbers of ST-HSCs and LT-HSCs in BM cells.
“Further analysis revealed that exposure to TBI did not significantly change the frequencies and numbers of ST-HSCs and LT-HSCs in BM cells (Figure 1B).”
Quote in the paperSubstantial claim - Findingown data§ Results
ROS production in HPCs and MPPs from irradiated mice was slightly higher (~1.2- to 1.3-fold) than in cells from unirradiated mice.
“As shown in Figure 5A and supplemental Figure 3A, ROS production in HPCs and MPPs from irradiated mice was slightly higher (∼1.2- to 1.3-fold) than in cells from unirradiated mice.”
Quote in the paperNot a substantial claim - Findingown data§ Results
After TBI, ROS production in irradiated HSCs including ST-HSCs and LT-HSCs was more than 1.7-fold higher than in respective unirradiated control cell populations.
“However, after TBI, ROS production in irradiated HSCs including ST-HSCs and LT-HSCs was more than 1.7-fold higher than in respective unirradiated control cell populations”
Quote in the paperSubstantial claim - Findingown data§ Results
Only about 12% of HSCs and 17% of LSK cells from irradiated mice exhibited significant increases in SA-β-gal staining 2 months after TBI.
“However, not all HSCs became senescent 2 months after TBI because only about 12% and 17% of HSCs and LSK cells from irradiated mice exhibited significant increases in SA-β-gal staining, respectively (Figure 3A and supplemental Figure 1)”
Quote in the paperNot a substantial claim
- Findingown data§ Results
More HSCs (particularly LT-HSCs) than MPPs were stained positive for SA-β-gal after TBI.
“Further analysis revealed that more HSCs (particularly LT-HSCs) than MPPs were stained positive for SA-β-gal after TBI”
Quote in the paperSubstantial claim - Findingown data§ Results
Increased cycling of irradiated LT-HSCs did not result in telomere shortening in HSCs and their progeny.
“however, this increased cycling did not result in telomere shortening in HSCs and their progeny (Figure 5D-F)”
Quote in the paperSubstantial claim - Findingcitation§ Results
Increased SA-β-gal staining after TBI was found mainly in LSK cells but not in HPCs.
“As we showed previously,8 increased SA-β-gal staining was found after TBI mainly in LSK cells but not in HPCs (Figure 3A and supplemental Figure 1).”
Quote in the paperSubstantial claim - Findingown data§ Results
Functional HSC frequencies measured by 4- and 6-week CAFCs were significantly lower in BM cells from irradiated mice than in normal controls.
“When measured by 4- and 6-week CAFCs, the frequencies of functional HSCs were significantly lower in BM cells from the irradiated mice than in those from normal controls (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data§ Results
In basal conditions, p16 and/or Arf KO mice had similar hematologic profiles as WT controls, including comparable frequencies and numbers of HPCs, LSK cells, MPPs, and HSCs in BM.
“In basal conditions, all of these KO mice had similar hematologic profiles as those of wild-type (WT) controls, including comparable frequencies and numbers of HPCs, LSK cells, MPPs, and HSCs in BM (Figure 6 and supplemental Figures 4 and 5).”
Quote in the paperSubstantial claim - Findingown data§ Results
Functional HPC frequencies measured by 1- and 2-week CAFCs were relatively normal in BM cells from irradiated mice compared with unirradiated controls.
“However, the frequencies of functional HPCs represented by 1- and 2-week CAFCs were relatively normal in BM cells from the irradiated mice compared with those from unirradiated controls (Figure 2A).”
Quote in the paperSubstantial claim - Findingown data§ Results
BM cells from irradiated p16 KO mice transplanted into lethally irradiated recipients demonstrated defects in HSC function similar to those of cells from irradiated WT mice.
“when BM cells from irradiated p16 KO mice were transplanted into lethally irradiated recipients, they demonstrated defects in HSC function that were similar to those of cells from irradiated WT mice”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Exposure of mice to a sublethal dose of TBI did not induce a reduction in the numbers of BM HSCs.
“exposure of mice to a sublethal dose of TBI did not induce a reduction in the numbers of BM HSCs”
Quote in the paperSubstantial claim - Findingown data§ Discussion
The long-term alterations in HSC functions included diminished ability to generate long-term donor cell engraftment after transplantation.
“including reduced clonogenicity, diminished ability to generate long-term donor cell engraftment after transplantation, and skewed differentiation toward myeloid lineages”
Quote in the paperSubstantial claim - Findingreasoning§ Discussion
Only a small fraction of HSCs became senescent at a time after TBI.
“only a small fraction of HSCs became senescent at a time after TBI”
Quote in the paperNot a substantial claim- Rests on an assumption: SA-β-gal and p16 are biomarkers for senescent cells.
- Findingown data§ Discussion
HSCs isolated from sublethally irradiated mice showed minimal changes in apoptosis compared with HSCs from unirradiated control animals.
“the cells showed minimal changes in apoptosis compared with HSCs from unirradiated control animals”
Quote in the paperSubstantial claim - Findingown data§ Discussion
SA-β-gal- LSK cells from irradiated mice exhibited some deficiencies in reproductive functions compared with control nonirradiated LSK cells.
“exhibited some deficiencies in reproductive functions”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
SA-β-gal- LSK cells from irradiated mice exhibited a significant reduction in long-term engraftment after transplantation compared with LSK cells from control mice.
“SA-β-gal– LSK cells from irradiated mice also exhibited a significant reduction in long-term engraftment after transplantation compared with LSK cells from control mice”
Quote in the paperSubstantial claim - Findingown data§ Discussion
SA-β-gal- LSK cells from irradiated mice, compared with control nonirradiated LSK cells, expressed slightly higher levels of p16.
“SA-β-gal– LSK cells from irradiated mice, compared with control nonirradiated LSK cells, also expressed slightly higher levels of p16”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
The long-term alterations in HSC functions included skewed differentiation toward myeloid lineages.
“including reduced clonogenicity, diminished ability to generate long-term donor cell engraftment after transplantation, and skewed differentiation toward myeloid lineages”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Increased production of ROS by irradiated HSCs was not associated with telomere shortening in HSCs and their progeny.
“increased production of ROS by irradiated HSCs was not associated with telomere shortening in HSCs and their progeny”
Quote in the paperSubstantial claim - Findingown data§ Discussion
The long-term alterations in HSC functions included reduced clonogenicity.
“including reduced clonogenicity, diminished ability to generate long-term donor cell engraftment after transplantation, and skewed differentiation toward myeloid lineages”
Quote in the paperSubstantial claim - Findingown data§ Results
HSCs from p16-Arf KO mice express no detectable p16 and Arf mRNA.
“HSCs from p16-Arf KO mice express no detectable p16 and Arf mRNA (supplemental Figure 6)”
Quote in the paperSubstantial claim - Findingown data§ Results
The defects in HSC function of BM cells from irradiated p16 KO mice included reduced long-term donor cell engraftment.
“including reduced long-term donor cell engraftment and myeloid lineage skewing (Figure 7)”
Quote in the paperSubstantial claim - Findingown data§ Results
The defects in HSC function of BM cells from irradiated p16 KO mice included myeloid lineage skewing.
“including reduced long-term donor cell engraftment and myeloid lineage skewing (Figure 7)”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Increased production of ROS was associated with a significant reduction in HSC quiescence after TBI.
“increased production of ROS was associated with a significant reduction in HSC quiescence”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Exposure of mice to a sublethal dose of TBI resulted in long-term alterations in HSC functions.
“resulted in long-term alterations in HSC functions”
Quote in the paperSubstantial claim - Findingown data§ Discussion
HSCs isolated from sublethally irradiated mice expressed increased levels of SA-β-gal and p16.
“HSCs isolated from the sublethally irradiated mice expressed increased levels of SA-β-gal and p16”
Quote in the paperSubstantial claim - Findingown data§ Results
Similar numbers of BM ST-HSCs and LT-HSCs from both WT and p16-Arf KO mice became SA-β-gal+ after TBI.
“similar numbers of BM ST-HSCs and LT-HSCs from both WT and p16-Arf KO mice became SA-β-gal+ after TBI (Figure 7D)”
Quote in the paperSubstantial claim - Findingown data§ Discussion
We did not detect significant increases in p21 and p18Ink4c (p18) mRNA expression in HSCs from irradiated p16/Arf KO mice.
“we did not detect significant increases in p21 and p18Ink4c (p18) mRNA expression in HSCs from irradiated p16/Arf KO mice (supplemental Figure 6)”
Quote in the paperSubstantial claim - Findingown data§ Discussion
A <tenfold increase in p15 mRNA expression was detected in HSCs from irradiated WT mice compared with control animals.
“a <tenfold increase in p15 mRNA expression was detected in HSCs from irradiated WT mice, compared with the cells from control animals (supplemental Figure 6)”
Quote in the paperNot a substantial claim - Findingown data§ Discussion
Knockout of p16 in mice had no significant effects on TBI-induced HSC senescence and residual BM suppression.
“knockout of p16 in mice had no significant effects on TBI-induced HSC senescence and residual BM suppression”
Quote in the paperSubstantial claim - Findingown data§ Discussion
Expression of p27 and p57 was not significantly elevated by TBI in HSCs from the KO mice.
“Nor was the expression of p27 and p57 significantly elevated by TBI in HSCs from the KO mice.”
Quote in the paperSubstantial claim - Findingown data§ Discussion
A >80-fold increase in the expression of p15Ink4b (p15) mRNA was observed in HSCs from irradiated p16/Arf KO mice compared with control animals.
“a >80-fold increase in the expression of p15Ink4b (p15) mRNA was observed in HSCs from irradiated p16/Arf KO mice”
Quote in the paperSubstantial claim - Findingown data§ Discussion
TBI caused a sustained increase in p21 expression in HSCs.
“TBI also caused a sustained increase in p21 expression in HSCs”
Quote in the paperSubstantial claim - Findingown data§ Discussion
HSCs from irradiated Arf and p16/Arf KO mice exhibited changes similar to those seen in cells from WT mice after TBI.
“HSCs from irradiated Arf and p16/Arf KO mice exhibited changes similar to those seen in the cells from WT mice after TBI”
Quote in the paperSubstantial claim - Interpretationown data§ Title
TBI causes long-term/residual bone marrow suppression/injury by selectively inducing HSC senescence.
“Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner”
- Also stated in: § Key Points · plain
“Total body irradiation causes long-term bone marrow suppression by selectively inducing HSC senescence.”
- Also stated in: § Results · hedged
“These findings suggest that TBI induced residual BM suppression, at least in part, via selective induction of HSC senescence.”
Quote in the paperSubstantial claim- The authors state this as an assumption: IR-induced residual BM injury has been attributed to induction of HSC senescence.
- Also stated in: § Key Points · plain
- Premisecitation§ Introduction
Some irradiated patients develop long-term or residual BM injuries manifested by decreases in HSC reserves and impairments in HSC self-renewal after recovering from IR-induced acute myelosuppression.
“However, some irradiated patients also develop long-term or residual BM injuries manifested by decreases in HSC reserves and impairments in HSC self-renewal after recovering from IR-induced acute myelosuppression.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Gardner, 2001, The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on primitive hematopoietic stem cell (PHSC) function and numbers, after chemotherapy., Exp Hematol source
Not checked in the free run.
- cites [5] van Os, 1998, Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents., Blood source
Not checked in the free run.
- Interpretationreasoning§ Results
HSCs mainly undergo premature senescence after exposure to IR.
“These findings suggest that HSCs mainly undergo premature senescence after exposure to IR.”
Quote in the paperSubstantial claim - Interpretationown data§ Key Points
TBI-induced HSC senescence is independent of p16Ink4a and Arf.
“The induction of HSC senescence is independent of telomere shortening and p16Ink4a and Arf.”
- Also stated in: § Results · plain
“Knockout of p16 and/or Arf fails to protect HSCs from TBI-induced senescence”
- Also stated in: § Results · hedged
“These findings suggest that p16 and Arf do not mediate induction of HSC senescence by TBI, even though TBI can upregulate their expression in HSCs.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Interpretationown data§ Results
TBI-induced HSC senescence is independent of telomere shortening.
“providing key evidence that TBI induces HSC senescence in a telomere shortening–independent manner.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
TBI can selectively induce chronic oxidative stress in HSCs.
“confirming that TBI can selectively induce chronic oxidative stress in HSCs.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression.
“However, genetic deletion of p16 and/or Arf had no effect on TBI-induced residual BM suppression and HSC senescence, because HSCs from irradiated p16 and/or Arf knockout (KO) mice exhibited changes similar to those seen in HSCs from wild-type mice after exposure to TBI.”
Quote in the paperSubstantial claim - Interpretationown data§ Results
LT-HSCs are highly responsive to ROS-stimulated cell proliferation.
“indicating that LT-HSCs are highly responsive to ROS-stimulated cell proliferation.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction
Knockout of the Arf gene alone provides no significant advantage for HSC/HPC expansion and self-renewal.
“Knockout of the Arf gene alone provides no significant advantage for HSC/HPC expansion and self-renewal,16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Lessard, 2003, Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells., Nature source
Not checked in the free run.
- Interpretationown data§ Discussion
ROS may mediate IR-induced HSC senescence in a telomere-independent manner.
“ROS may mediate IR-induced HSC senescence in a telomere-independent manner”
Quote in the paperSubstantial claim - Interpretationown data§ Results
IR induces residual BM suppression in a p16/Arf-independent manner.
“these data demonstrate that IR induces residual BM suppression and HSC senescence in a p16/Arf-independent manner”
Quote in the paperSubstantial claim - Premisecitation§ Discussion
A negative bystander effect of TBI on HSCs plays a role in IR-induced residual BM injury.
“damage to the HSC niche, such as induction of BM stromal cell senescence, and a negative bystander effect of TBI on HSCs, also play a role in IR-induced residual BM injury.32,33”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Shen, 2012, An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells., Blood source
Not checked in the free run.
- Interpretationown data§ Results
IR induces HSC senescence in a p16/Arf-independent manner.
“these data demonstrate that IR induces residual BM suppression and HSC senescence in a p16/Arf-independent manner”
Quote in the paperSubstantial claim- Rests on an assumption: SA-β-gal and p16 are biomarkers for senescent cells.
- Interpretationown data§ Discussion
Some of these changes are likely attributable to induction of HSC senescence.
“Some of these changes are likely attributable to induction of HSC senescence.”
Quote in the paperSubstantial claim- Rests on an assumption: SA-β-gal and p16 are biomarkers for senescent cells.
- Premisecitation§ Discussion
Damage to the HSC niche, such as induction of BM stromal cell senescence, plays a role in IR-induced residual BM injury.
“damage to the HSC niche, such as induction of BM stromal cell senescence, and a negative bystander effect of TBI on HSCs, also play a role in IR-induced residual BM injury.32,33”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Carbonneau, 2012, Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis., Blood source
Not checked in the free run.
- Premisecitation§ Results
Increased expression of p21 also plays a role in induction of senescence, particularly during its initiation.
“Increased expression of p21 also plays a role in induction of senescence, particularly during its initiation.26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Pantoja, 1999, Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras., Oncogene source
Not checked in the free run.
- Interpretationcitation§ Discussion
The small fraction of senescent HSCs may be in part attributable to immunosurveillance of senescent cells by immune cells that can rapidly remove senescent cells to prevent accumulation in vivo.
“This may be in part attributable to the immunosurveillance of senescent cells by immune cells that can rapidly remove senescent cells to prevent the accumulation of senescent cells in vivo.34”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Krizhanovsky, 2008, Senescence of activated stellate cells limits liver fibrosis., Cell source
Not checked in the free run.
- Premisecitation§ Discussion
Treating irradiated mice with various antioxidants after IR significantly attenuated TBI-induced LSK cell senescence and residual BM suppression.
“Treating the irradiated mice with various antioxidants after IR significantly attenuated TBI-induced LSK cell senescence and residual BM suppression.9,30”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [9] Li, 2011, Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression., Free Radic Biol Med source
Not checked in the free run.
- cites [30] Wang, 2011, Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury., Radiat Res source
Not checked in the free run.
- Premisecitation§ Discussion
IR-induced residual BM injury can deteriorate to become hypoplastic anemia or myelodysplastic syndrome over time or after additional treatment with IR and/or chemotherapy or undergoing autologous BM transplantation.
“IR-induced residual BM injury can deteriorate to become hypoplastic anemia or myelodysplastic syndrome over time or after additional treatment with IR and/or chemotherapy or undergoing autologous BM transplantation.1,2”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Mauch, 1995, Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy., Int J Radiat Oncol Biol Phys source
Not checked in the free run.
- cites [2] Testa, 1985, Long-term bone marrow damage in experimental systems and in patients after radiation or chemotherapy., Anticancer Res
Not checked in the free run.
- Rests on an assumption: The mouse model of TBI is relevant to human IR-induced residual BM injury.
- Premisecitation§ Discussion
Exposure of mice to TBI induced persistent increases in ROS production in HSC-enriched LSK cells, in part via upregulation of nicotinamide adenine dinucleotide phosphate-oxidase 4.
“exposure of mice to TBI induced persistent increases in ROS production in HSC-enriched LSK cells, in part via upregulation of nicotinamide adenine dinucleotide phosphate-oxidase 4.23”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Wang, 2010, Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells., Free Radic Biol Med source
Not checked in the free run.
- Premisecitation§ Discussion
Activation of p38 was involved in IR-induced BM hematopoietic cell senescence and dysfunction.
“activation of p38 was involved in IR-induced BM hematopoietic cell senescence and dysfunction.30,40”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [30] Wang, 2011, Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury., Radiat Res source
Not checked in the free run.
- cites [40] Li, 2011, Mitigation of ionizing radiation-induced bone marrow suppression by p38 inhibition and G-CSF administration., J Radiat Res (Tokyo) source
Not checked in the free run.
- Interpretationown data§ Discussion
Induction of HSC senescence by IR was independent of p16.
“induction of HSC senescence by IR was independent of p16”
Quote in the paperSubstantial claim- Rests on an assumption: SA-β-gal and p16 are biomarkers for senescent cells.
- Interpretationown data§ Discussion
The results from this study provide important new insights into the mechanism by which IR causes long-term BM suppression via induction of premature senescence of HSCs in a p16-Arf-independent manner.
“the results from this study provide important new insights into the mechanism by which IR causes long-term BM suppression via induction of premature senescence of HSCs in a p16-Arf–independent manner”
Quote in the paperSubstantial claim- Rests on an assumption: SA-β-gal and p16 are biomarkers for senescent cells.
- Interpretationreasoning§ Discussion
p16/Arf can mediate induction of cellular senescence in a manner dependent on cell type and cell context.
“p16/Arf can mediate induction of cellular senescence in a manner dependent on cell type and cell context”
Quote in the paperSubstantial claim - Interpretationown data§ Discussion
The lack of effect of p16 deletion cannot be attributed to compensation by Arf.
“the lack of effect of p16 deletion cannot be attributed to compensation by Arf”
Quote in the paperSubstantial claim
- May combine two claims. 20
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 37
May combine two claims.
Findingown data§ ResultsExpression of p21 mRNA, but not p27 and p57 mRNA, was moderately higher in HSCs from irradiated mice than in controls.
“In addition, expression of p21 mRNA, but not that of p27 and p57 mRNA, was also moderately higher in HSCs from irradiated mice than in those from control mice.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ ResultsTwo months after 6 Gy TBI, HPC frequencies and numbers in irradiated mice nearly reached normal levels, but LSK cell frequencies and numbers remained significantly lower than controls.
“The results from this assay revealed that the frequencies and numbers of HPCs (Lin–Sca1–c-kit+ cells) in the irradiated mice had nearly reached normal levels, but the frequencies and numbers of LSK cells in these mice remained significantly lower than those in controls (Figure 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsThe reduction in LSK cells after TBI was mainly due to a significant reduction in MPPs, while HSC levels were relatively normal.
“These changes in LSK cells were mainly attributed to the significant reduction in MPPs because the level of HSCs was relatively normal in the irradiated mice (Figure 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsHSCs from irradiated mice exhibited significant functional defects after transplantation into lethally irradiated recipients, including reduced long-term donor cell engraftment and myeloid lineage skewing.
“Furthermore, after transplantation into lethally irradiated recipients (Figure 2B), HSCs from irradiated mice exhibited significant functional defects compared with normal HSCs, including reduced ability to generate long-term donor cell engraftment and myeloid lineage skewing (Figure 2C-D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsSA-β-gal- LSK cells from irradiated mice expressed slightly higher levels of p16 and exhibited some deficiencies in proliferative and repopulating functions compared with control unirradiated LSK cells.
“In addition, SA-β-gal– LSK cells from irradiated mice also expressed slightly higher levels of p16 and exhibited some deficiencies in their proliferative and repopulating functions compared with those of control unirradiated LSK cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ ResultsIncreased production of ROS in irradiated LT-HSCs was associated with a significant reduction in cell quiescence (fewer G0 cells) and an increase in DNA synthesis (more BrdU-labeled cells).
“The increased production of ROS in irradiated LT-HSCs was associated with a significant reduction in cell quiescence (eg, fewer G0 cells) and an increase in DNA synthesis (eg, more BrdU-labeled cells) (Figure 5B-C and supplemental Figure 3B-C)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsIrradiated HSCs expressed about 18-fold higher levels of p16 and 14-fold higher levels of Arf mRNA than unirradiated HSCs.
“This suggestion is supported by the finding that irradiated HSCs expressed about 18-fold higher levels of p16 and 14-fold higher levels of Arf mRNA than did unirradiated HSCs (Figure 3C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsBefore TBI, BM cells from KO mice generated similar numbers of various CAFCs; after TBI, they exhibited comparable reductions in HSC clonogenicity, manifested by decreases in 4- and 6-week CAFCs, similar to those seen in cells from irradiated WT mice.
“Before exposure to TBI, BM cells from the KO mice also generated similar numbers of various CAFCs; after TBI, they exhibited comparable reductions in HSC clonogenicity, manifested by decreases in 4- and 6-week CAFCs, which were similar to those seen in cells from irradiated WT mice (Figure 7A-C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsTwo months after TBI, p16 and/or Arf KO mice exhibited the same degrees of reductions in BM LSK cells and MPPs, with no significant changes in HPCs and HSCs, except p16 KO mice showed a significant reduction in HSCs after TBI compared with unirradiated controls.
“Two months after TBI, they also exhibited the same degrees of reductions in BM LSK cells and MPPs, with no significant changes in HPCs and HSCs, except that p16 KO mice showed a significant reduction in HSCs after TBI, compared with unirradiated controls.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ ResultsSA-β-gal+ LSK cells expressed significantly higher levels of p16, exhibited diminished ability to proliferate in vitro, and produced substantially lower long-term engraftment after transplantation compared with SA-β-gal- LSK cells and control unirradiated LSK cells.
“As is shown in Figure 3D-F and Figure 4A-C, SA-β-gal+ LSK cells expressed significantly higher levels of p16, exhibited diminished ability to proliferate in vitro, and produced substantially lower levels of long-term engraftment after transplantation compared with SA-β-gal– LSK cells and LSK cells from control unirradiated mice.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data§ DiscussionIncreased production of ROS was associated with an increase in HSC proliferation after TBI.
“an increase in HSC proliferation after TBI”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionBM suppression is one of the common side effects of radiotherapy and the primary cause of death after exposure to a moderate or high dose of TBI.
“Bone marrow (BM) suppression is one of the common side effects of radiotherapy and the primary cause of death after exposure to a moderate or high dose of total body irradiation (TBI).1,2”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Mauch, 1995, Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy., Int J Radiat Oncol Biol Phys source
Not checked in the free run.
- cites [2] Testa, 1985, Long-term bone marrow damage in experimental systems and in patients after radiation or chemotherapy., Anticancer Res
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionAcute BM suppression occurs within days after exposure to IR, primarily as a result of induction of apoptosis in rapidly proliferating HPCs.
“Acute BM suppression occurs within days after exposure to ionizing radiation (IR), primarily as a result of induction of apoptosis in the rapidly proliferating hematopoietic progenitor cells (HPCs).3”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Mohrin, 2010, Hematopoietic stem cell quiescence promotes error-prone DNA repair and mutagenesis., Cell Stem Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionResidual BM injury can predispose irradiated individuals to develop leukemia and lymphoma by reducing the fitness of HSCs.
“In addition, residual BM injury can predispose irradiated individuals to develop leukemia and lymphoma by reducing the fitness of HSCs.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Marusyk, 2010, Irradiation selects for p53-deficient hematopoietic progenitors., PLoS Biol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThe use of HGFs may worsen IR-induced residual BM damage by promoting proliferation and differentiation of HSCs and HPCs at the expense of HSC self-renewal.
“In fact, the use of HGFs may worsen IR-induced residual BM damage by promoting proliferation and differentiation of HSCs and HPCs at the expense of HSC self-renewal.6”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] van Os, 2000, Granulocyte-colony stimulating factor impedes recovery from damage caused by cytotoxic agents through increased differentiation at the expense of self-renewal., Stem Cells source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ IntroductionResidual BM damage is latent, long lasting, shows little tendency for recovery, and can lead to hypoplastic anemia or myelodysplastic syndrome at a later time or after additional hematopoietic stress.
“Although residual BM damage is latent, it is long lasting, shows little tendency for recovery, and can lead to the development of hypoplastic anemia or a myelodysplastic syndrome at a later time or after additional hematopoietic stress.4,5”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Gardner, 2001, The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on primitive hematopoietic stem cell (PHSC) function and numbers, after chemotherapy., Exp Hematol source
Not checked in the free run.
- cites [5] van Os, 1998, Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents., Blood source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThe biological action of Arf relies on the p53 pathway because Arf can directly bind to MDM2 and cause accumulation of p53 by segregating MDM2 from p53 and by inhibiting MDM2's E3 ubiquitin protein ligase activity for p53.
“In contrast, the biological action of Arf relies on the p53 pathway. This is because Arf can directly bind to mouse double minute 2 homolog (MDM2) and cause the accumulation of p53 by segregating MDM2 from p53 and by inhibiting MDM2’s E3 ubiquitin protein ligase activity for p53.10,11,14”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [10] Lowe, 2003, Tumor suppression by Ink4a-Arf: progress and puzzles., Curr Opin Genet Dev source
Not checked in the free run.
- cites [11] Sharpless, 1999, The INK4A/ARF locus and its two gene products., Curr Opin Genet Dev source
Not checked in the free run.
- cites [14] Sherr, 2000, The ARF/p53 pathway., Curr Opin Genet Dev source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Introductionp16 functions as a cyclin-dependent kinase (CDK) 4/6 inhibitor.
“p16 functions as a cyclin-dependent kinase (CDK) 4/6 inhibitor.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Lowe, 2003, Tumor suppression by Ink4a-Arf: progress and puzzles., Curr Opin Genet Dev source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionBy inhibiting CDK4/6 activity, p16 causes retinoblastoma protein hypophosphorylation and suppresses expression of E2F-dependent genes, resulting in restriction of G1/S cell cycle progression and induction of senescence.
“By inhibiting CDK4/6 activity, p16 causes retinoblastoma protein (Rb) hypophosphorylation and suppresses expression of E2F-dependent genes,13 resulting in restriction of G1/S cell cycle progression and induction of senescence.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Narita, 2003, Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence., Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ ResultsInduction of cellular senescence occurs as a result of extensive replication, which results in telomere shortening or which occurs prematurely after cells are exposed to oxidative, genotoxic, or oncogenic stress.
“Induction of cellular senescence occurs as a result of extensive replication, which results in telomere shortening or which occurs prematurely after cells are exposed to oxidative, genotoxic, or oncogenic stress.27-29”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [27] Serrano, 2001, Putting the stress on senescence., Curr Opin Cell Biol source
Not checked in the free run.
- cites [28] Marcotte, 2002, Replicative senescence revisited., J Gerontol A Biol Sci Med Sci source
Not checked in the free run.
- cites [29] Hayflick, 1965, The Limited in Vitro Lifetime of Human Diploid Cell Strains., Exp Cell Res source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ ResultsIncreased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.
“Increased expression of p16 and Arf has been implicated in mediating induction of senescence in a variety of cells including HSCs and is the most robust biomarker of senescence cells besides SA-β-gal staining.8,24,25”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [8] Wang, 2006, Total body irradiation selectively induces murine hematopoietic stem cell senescence., Blood source
Not checked in the free run.
- cites [24] Dimri, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo., Proc Natl Acad Sci USA source
Not checked in the free run.
- cites [25] Krishnamurthy, 2004, Ink4a/Arf expression is a biomarker of aging., J Clin Invest source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ IntroductionUpregulation of p16 and Arf has been implicated in mediating the induction of cellular senescence in a variety of cells including HSCs.
“Upregulation of p16 and Arf has been implicated in mediating the induction of cellular senescence in a variety of cells including HSCs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Park, 2003, Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells., Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionActivation of p53 by Arf can induce not only senescence but also apoptosis, depending on which gene downstream of p53 is induced after p53 activation.
“Therefore, activation of p53 by Arf can induce not only senescence but also apoptosis, depending on which gene downstream of p53 is induced after p53 activation.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [10] Lowe, 2003, Tumor suppression by Ink4a-Arf: progress and puzzles., Curr Opin Genet Dev source
Not checked in the free run.
- cites [11] Sharpless, 1999, The INK4A/ARF locus and its two gene products., Curr Opin Genet Dev source
Not checked in the free run.
- cites [14] Sherr, 2000, The ARF/p53 pathway., Curr Opin Genet Dev source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introductionp16, but not Arf, plays an important role in mediating induction of Bmi1−/− HSC senescence, whereas Arf mainly promotes HSC apoptosis.
“However, it appears that p16, but not Arf, plays an important role in mediating induction of Bmi1−/− HSC senescence, whereas Arf mainly promotes HSC apoptosis.15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Park, 2003, Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells., Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ IntroductionKnockout of both the p16 and Arf genes in mice significantly increases the clonal expansion of HSCs in vitro but modestly promotes HSC self-renewal in vivo.
“In addition, it has been found that knockout of both the p16 and Arf genes in mice significantly increases the clonal expansion of HSCs in vitro but modestly promotes HSC self-renewal in vivo.16”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Lessard, 2003, Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells., Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introductionp16 plays a more significant role than Arf in regulating HSC self-renewal and inducing HSC senescence, even though both proteins are overexpressed in senescent HSCs.
“These findings suggest that p16 plays a more significant role than Arf in regulating HSC self-renewal and inducing HSC senescence, even though both proteins are overexpressed in senescent HSCs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionThe p16-Arf locus encodes 2 tumor suppressors, p16 and Arf.
“The p16-Arf locus encodes 2 tumor suppressors, p16 and Arf.10-12”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [10] Lowe, 2003, Tumor suppression by Ink4a-Arf: progress and puzzles., Curr Opin Genet Dev source
Not checked in the free run.
- cites [11] Sharpless, 1999, The INK4A/ARF locus and its two gene products., Curr Opin Genet Dev source
Not checked in the free run.
- cites [12] Cheng, 2004, Cell cycle inhibitors in normal and tumor stem cells., Oncogene source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ IntroductionKnockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.
“but knockout of p16 increases the life-span of HSCs by promoting HSC self-renewal.16-19”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [16] Lessard, 2003, Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells., Nature source
Not checked in the free run.
- cites [17] Lewis, 2001, The influence of INK4 proteins on growth and self-renewal kinetics of hematopoietic progenitor cells., Blood source
Not checked in the free run.
- cites [18] Stepanova, 2005, A limited role for p16Ink4a and p19Arf in the loss of hematopoietic stem cells during proliferative stress., Blood source
Not checked in the free run.
- cites [19] Janzen, 2006, Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a., Nature source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ IntroductionInactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM−/− HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.20,21”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [20] Ito, 2004, Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells., Nature source
Not checked in the free run.
- cites [21] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionMutation of the ataxia telangiectasia mutated (ATM) gene results in upregulation of p16 and Arf in HSCs.
“Furthermore, mutation of the ataxia telangiectasia mutated (ATM) gene also results in upregulation of p16 and Arf in HSCs.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [20] Ito, 2004, Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells., Nature source
Not checked in the free run.
- cites [21] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ IntroductionIncreased expression of p16 and Arf was found in HSCs from Bmi1−/− mice.
“For example, increased expression of p16 and Arf was found in HSCs from Bmi1−/− mice.15”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Park, 2003, Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells., Nature source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ ResultsPrevious studies suggest that IR induces HSC senescence primarily via induction of oxidative stress.
“Our previous studies suggest that IR induces HSC senescence primarily via induction of oxidative stress,9,23,30”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9] Li, 2011, Mn(III) meso-tetrakis-(N-ethylpyridinium-2-yl) porphyrin mitigates total body irradiation-induced long-term bone marrow suppression., Free Radic Biol Med source
Not checked in the free run.
- cites [23] Wang, 2010, Total body irradiation causes residual bone marrow injury by induction of persistent oxidative stress in murine hematopoietic stem cells., Free Radic Biol Med source
Not checked in the free run.
- cites [30] Wang, 2011, Inhibition of p38 MAPK attenuates ionizing radiation-induced hematopoietic cell senescence and residual bone marrow injury., Radiat Res source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ DiscussionLong-term cancer survivors are at increased risk for developing late effects related to cancer treatment, including IR-induced residual BM injury.
“long-term cancer survivors are at increased risk for developing late effects related to cancer treatment, including IR-induced residual BM injury”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Mauch, 1995, Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy., Int J Radiat Oncol Biol Phys source
Not checked in the free run.
- cites [2] Testa, 1985, Long-term bone marrow damage in experimental systems and in patients after radiation or chemotherapy., Anticancer Res
Not checked in the free run.
- Rests on an assumption: The mouse model of TBI is relevant to human IR-induced residual BM injury.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.
“ROS plays an important role in mediating induction of HSC senescence under various pathological conditions, such as mutation of ATM and various Fanconi anemia genes; deletion of Bmi1, FoxOs, Mdm2, and Tsc1; and aging.15,19,20,35-38”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [15] Park, 2003, Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells., Nature source
Not checked in the free run.
- cites [19] Janzen, 2006, Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a., Nature source
Not checked in the free run.
- cites [20] Ito, 2004, Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells., Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionInduction of HSC differentiation in response to IR-induced DNA damage via activation of the G-CSF/Stat3/BATF-dependent differentiation checkpoint contributes to IR-induced myeloid-skewed HSCs by selectively depleting lymphoid-biased HSCs.
“induction of HSC differentiation in response to IR-induced DNA damage via activation of the granulocyte colony-stimulating factor/Stat3/BATF–dependent differentiation checkpoint also contribute to IR-induced myeloid-skewed HSCs by selectively depleting lymphoid-biased HSCs, as was recently reported.31”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Wang, 2012, A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage., Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionEctopic expression of manganese superoxide dismutase and catalase in HSCs reduces IR-induced HSC injury.
“ectopic expression of manganese superoxide dismutase and catalase in HSCs reduces IR-induced HSC injury.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Miao, 2013, Hematopoietic stem cell regeneration enhanced by ectopic expression of ROS-detoxifying enzymes in transplant mice., Mol Ther source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Discussionp21 upregulation protected HSCs against IR by limiting IR-induced DNA damage and p53 activation and by promoting HSC cell cycle entry and self-renewing expansion.
“p21 upregulation actually protected HSCs against IR by limiting IR-induced DNA damage and p53 activation and by promoting HSC cell cycle entry and self-renewing expansion, suggesting that p21 and p16 may have opposite effects on IR-induced HSC senescence.46-48”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [46] Insinga, 2013, DNA damage in stem cells activates p21, inhibits p53, and induces symmetric self-renewing divisions., Proc Natl Acad Sci USA source
Not checked in the free run.
- cites [47] Baker, 2013, p21 both attenuates and drives senescence and aging in BubR1 progeroid mice., Cell Rep source
Not checked in the free run.
- cites [48] Johnson, 2010, Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition., J Clin Invest source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ Discussionp21 and p16 may have opposite effects on IR-induced HSC senescence.
“p21 upregulation actually protected HSCs against IR by limiting IR-induced DNA damage and p53 activation and by promoting HSC cell cycle entry and self-renewing expansion, suggesting that p21 and p16 may have opposite effects on IR-induced HSC senescence.46-48”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionIR induced senescence in BM stromal cells in a p16- and Arf-dependent manner.
“IR induced senescence in BM stromal cells in a p16- and Arf-dependent manner.32”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Carbonneau, 2012, Ionizing radiation-induced expression of INK4a/ARF in murine bone marrow-derived stromal cell populations interferes with bone marrow homeostasis., Blood source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussionp38 plays an important role in regulating HSC self-renewal.
“p38 plays an important role in regulating HSC self-renewal”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med source
Not checked in the free run.
- cites [36] Miyamoto, 2007, Foxo3a is essential for maintenance of the hematopoietic stem cell pool., Cell Stem Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionSimilar results were observed in senescent HSCs from Atm-mutated mice.
“Similar results were also observed recently in senescent HSCs from Atm-mutated mice.21”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionActivation of p38 by oxidative stress can mediate induction of HSC senescence in Atm mutants and FoxO3 KO mice via upregulation of p16.
“activation of p38 by oxidative stress can mediate induction of HSC senescence in Atm mutants and FoxO3 KO mice via upregulation of p16.21,36”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [21] Ito, 2006, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med source
Not checked in the free run.
- cites [36] Miyamoto, 2007, Foxo3a is essential for maintenance of the hematopoietic stem cell pool., Cell Stem Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionEarly T-lymphoid progenitors are very sensitive to p16 upregulation for induction of senescence during aging.
“are very sensitive to p16 upregulation for induction of senescence during aging.42,43”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Liu, 2009, Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging., Aging Cell source
Not checked in the free run.
- cites [43] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Dev source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Discussionp18 can negatively regulate HSC self-renewal.
“p18 can also negatively regulate HSC self-renewal.49”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [49] Yu, 2006, Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners., Blood source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ DiscussionUpregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging.
“upregulation of p16 and Arf has been implicated in mediating induction of HSC senescence in a variety of pathological conditions and during aging,8,41,42”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [8] Wang, 2006, Total body irradiation selectively induces murine hematopoietic stem cell senescence., Blood source
Not checked in the free run.
- cites [41] Liu, 2011, Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes., Blood source
Not checked in the free run.
- cites [42] Liu, 2009, Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging., Aging Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ DiscussionROS may mediate IR-induced premature senescence of HSCs via activation of the p38-p16 pathway.
“ROS may mediate IR-induced premature senescence of HSCs via activation of the p38-p16 pathway”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionIncreased expression of p21 has been implicated in induction of cellular senescence independent of p16.
“increased expression of p21 has been implicated in induction of cellular senescence independent of p16.44,45”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [44] de Keizer, 2010, Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence., Cancer Res source
Not checked in the free run.
- cites [45] Takeuchi, 2010, Intrinsic cooperation between p16INK4a and p21Waf1/Cip1 in the onset of cellular senescence and tumor suppression in vivo., Cancer Res source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DiscussionEarly T-lymphoid progenitors are exquisitely dependent on CDK4/6 activity.
“early T-lymphoid progenitors are exquisitely dependent on CDK4/6 activity”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Liu, 2009, Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging., Aging Cell source
Not checked in the free run.
- cites [43] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Dev source
Not checked in the free run.
The authors state this as an assumption.
IR-induced residual BM injury has been attributed to induction of HSC senescence.
“IR-induced residual BM injury has been attributed to induction of HSC senescence. This assumption is supported by our recent findings that LSK cells (ie, Lin–Sca1+c-kit+) isolated from the BM of sublethally irradiated mice expressed increased levels of biomarkers for senescent cells, such as SA-β-gal and p16.8,9”
The paper relies on this without support.
LSK cells are heterogeneous and only a small proportion of the LSK population is made up of HSCs, with the rest being composed of multipotent progenitor cells (MPPs).
“However, LSK cells are heterogeneous and only a small proportion of the LSK population is made up of HSCs, with the rest being composed of multipotent progenitor cells (MPPs).”
The paper relies on this without support.
The mechanisms by which IR induces residual BM suppression have not been clearly defined.
“However, the mechanisms by which IR induces residual BM suppression have not been clearly defined, which hampers development of effective treatments to ameliorate the injury.”
The paper relies on this without support.
It is not known whether TBI actually induces HSC senescence.
“It is not known whether TBI actually induces HSC senescence.”
The paper relies on this without support.
SA-β-gal and p16 are biomarkers for senescent cells.
“two of the most widely used biomarkers for senescent cells”
The paper relies on this without support.
The mouse model of TBI is relevant to human IR-induced residual BM injury.
“in the present study, we investigated how residual BM suppression was induced by IR in a mouse model”
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?
Ageing and genotoxic stress induce cellular senescence of haematopoietic stem cells and osteoprogenitor cells, with subsequent decline in their functions in both mice and humans.
“Ageing and genotoxic stress induce cellular senescence of these stem cells 96,97 and osteoprogenitor cells, 98,99 with subsequent decline in the functions of these cells in both mice and humans.100”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [96]
Cites
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477 · see citing works
The limited in vitro lifetime of human diploid cell strains
Hayflick, L. (1965) · Experimental Cell Research · doi:10.1016/0014-4827(65)90211-9 · Cited by 5,876 · see citing works
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · see citing works
Senescence of activated stellate cells limits liver fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.06.049 · Cited by 2,029 · see citing works
Senescence of Activated Stellate Cells Limits Liver Fibrosis
Krizhanovsky, V., Yon, M., Dickins, R. A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., & Lowe, S. W. (2008) · Cell · doi:10.1016/j.cell.2008.09.015 · Cited by 2,027
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Ink4a/Arf expression is a biomarker of aging
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Self-citationBmi-1 determines the proliferative capacity of normal and leukaemic stem cells.
Lessard, J., & Sauvageau, G. (2003) · Nature · doi:10.1038/nature01572 · Cited by 1,452 · see citing works
Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Takubo, K., Matsuoka, S., Miyamoto, K., Ohmura, M., Naka, K., Hosokawa, K., Ikeda, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1388 · Cited by 1,362 · see citing works
Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
Ito, K., Hirao, A., Arai, F., Matsuoka, S., Takubo, K., Hamaguchi, I., Nomiyama, K., Hosokawa, K., Sakurada, K., Nakagata, N., et al. (2004) · Nature · doi:10.1038/nature02989 · Cited by 1,175 · cited 2× · see citing works
“Inactivation of the p16-Rb pathway restores the reproductive function of ATM HSCs, whereas inhibition of the Arf-p53 pathway has no such effect.(20,21) These findings suggest that p16 plays a more significant role than Arf in regulating HSC self-renewal and inducing HSC senescence, even though both proteins are overex…”
BackgroundStem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Janzen, V., Forkert, R., Fleming, H. E., Saito, Y., Waring, M. T., Dombkowski, D. M., Cheng, T., DePinho, R. A., Sharpless, N. E., & Scadden, D. T. (2006) · Nature · doi:10.1038/nature05159 · Cited by 1,106 · see citing works
Self-citationFoxo3a is essential for maintenance of the hematopoietic stem cell pool
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- Authors
- Shao, L., Feng, W., Li, H., Gardner, D., Luo, Y., Wang, Y., Liu, L., Meng, A., Sharpless, N. E., & Zhou, D.
- Affiliations
- University of Arkansas for Medical Sciences (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Medical University of South Carolina (US)
- University of North Carolina at Chapel Hill (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2014-05-15
- Volume
- 123
- Issue
- 20
- Pages
- 3105-3115
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC4023419
- OpenAlex
- W2026212073
- Semantic Scholar
- 55755e0cc8514399ee8894e659b88c39f634ee7e
- Cited by
- 165
- References
- 51
- Citations by year
- 2026: 5 · 2025: 13 · 2024: 8 · 2023: 14 · 2022: 15 · 2021: 18 · 2020: 11 · 2019: 17 · 2018: 9 · 2017: 11 · 2016: 15 · 2015: 23 · 2014: 6
- FWCI
- 13.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Medical University of South Carolina
- Arkansas Research Alliance
- Edward P. Evans Foundation
- Evans Medical Foundation
- National Natural Science Foundation of China
- National Institutes of Health
- National Cancer Institute (R01CA122023, P30CA016086)
- National Institute of Allergy and Infectious Diseases (R01AI080421, AI080421)
- National Institute of Environmental Health Sciences (P30ES010126)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- total body irradiation, hematopoietic stem cells, premature senescence, p16INK4a, ARF, senescence-associated β-galactosidase, reactive oxygen species, long-term engraftment, clonogenic activity, hematopoietic stem cell self-renewal, myeloid skewing
- MeSH terms
- Animals, Bone Marrow, Cells, Cultured, Hematopoietic Stem Cells, Mice, Inbred C57BL, Whole-Body Irradiation, Telomere, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice, Gene Knockout Techniques
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