2015
DOI: 10.1038/ncomms7328
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Small-molecule inhibitors targeting INK4 protein p18INK4C enhance ex vivo expansion of haematopoietic stem cells

Abstract: Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico scre… Show more

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Cited by 48 publications
(51 citation statements)
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“…However, the significant effect of p18 absence on HSC cannot be solely explained by its classical role in cell cycle regulation, as deletion of p18 did not significantly affect the cell cycle profile of HSCs despite its profound effect on HSC engraftment and reconstitution in recipient mice [49]. Interestingly, our recent work demonstrated a specific role of small molecule inhibitors for p18 protein on HSC expansion, indicating the potential value of targeting p18 for therapeutic expansion of HSC [49,51].…”
Section: P18mentioning
confidence: 99%
See 1 more Smart Citation
“…However, the significant effect of p18 absence on HSC cannot be solely explained by its classical role in cell cycle regulation, as deletion of p18 did not significantly affect the cell cycle profile of HSCs despite its profound effect on HSC engraftment and reconstitution in recipient mice [49]. Interestingly, our recent work demonstrated a specific role of small molecule inhibitors for p18 protein on HSC expansion, indicating the potential value of targeting p18 for therapeutic expansion of HSC [49,51].…”
Section: P18mentioning
confidence: 99%
“…Deficiency of p18 results in an expansion of stem and progenitor cells, which show a competitive advantage in serial bone marrow transplantation assays compared with that of normal controls [47,48]. Among all the CKIs, p18 appears to have the strongest impact on HSC self-renewal in mice [49]. Regarding its mechanism, it has been proposed that HSCs have a shorter G1 phase due to a lower cyclin D/ CDK4 threshold activity.…”
Section: P18mentioning
confidence: 99%
“…60 Cell cycle regulator (CKI) also plays a vital role in stem cell manipulation; two inhibitors of CKI p18 INK4C , P18IN003 and P18IN011, are known to induce HSC expansion. 19 Other molecules that induce HSC expansion are advancing through clinical trials, including TEPA (copper chelate), 73 SR1 (AhR antagonist), 74 and Nicord (SIRT1 inhibitor). 75 These compounds have completed phase I/II and are now in phase II/III multicenter clinical trials 76 (Figure 3D).…”
Section: Resultsmentioning
confidence: 99%
“…The number of published studies focusing on stem cell-related signaling pathways and small molecule modulators is steadily increasing, while generating the experimental data required to find, associate, and validate reported active compounds can be slow and challenging. 2,19 …”
Section: Introductionmentioning
confidence: 99%
“…p18 [144] as a speciic inhibitor of cyclin-dependent kinase (CDK) is a potential direct target of cell cycle regulation. Two small-molecule compounds P18IN003 and P18IN011 were identiied in this study as being able to enhance the proliferation of mouse HSC cells and increase the reconstitution to bone marrow by at least threefold.…”
Section: Further Cytokine and Small Molecule Addition To Expand Umentioning
confidence: 99%