Elsevier

Stem Cell Research

Volume 44, April 2020, 101759
Stem Cell Research

p57Kip2 is a master regulator of human adipose derived stem cell quiescence and senescence

https://doi.org/10.1016/j.scr.2020.101759Get rights and content
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  • In the present study, we aim to explore key molecular mechanisms underlying hADSCs proliferation and senescence, two of the most important aspects in their clinical applications. We found that p57Kip2 was highly expressed in freshly isolated presumably quiescent hADSCs but rapidly depleted as hADSCs became proliferative in vitro. Intriguingly p57Kip2 expression was higher in hADSCs isolated from the aged individual that transited more slowly to be proliferative. The induction of p57Kip2 in quiescent and senescent ADSCs was confirmed by in vitro serum starvation models and RNA-seq data respectively. In line with its expression dynamics, ectopic expression of p57Kip2 promoted hADSCs cycle arrest while knockdown of p57Kip2 disrupted ADSCs quiescence even under serum starvation. As a master regulator, p57Kip2 does so by modulating major cell cycle players such as cyclin E1 and CDK2. Knockdown of p57Kip2 restored the expression of cyclin E1 and CDK2 even under serum starvation and overexpression of p57 repressed their expression under proliferative condition.

  • Taken together our present work has demonstrated a key role for p57Kip2 in hADSCs quiescence and senescence through modulating key cell cycle molecules. Further work should be directed at dissecting its mechanisms in details and exploring innovative strategies for efficient cell amplification, better quality and therapeutic efficacy. As such, our work provides crucial and timely insights to hADSCs biology of strong clinical relevance. It shall be of strong interest to a diverse readership in the field of stem cell biology and regenerative medicine.

Abstract

Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57Kip2, a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57Kip2 overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the CDK2–CyclinE1 complex. Given its key role in quiescence and senescence, p57Kip2 may be exploited for innovative strategies to amplify hADSCs of high quality for clinics.

Keywords

Human adipose derived stem cells
p57Kip2
Quiescence
Senescence

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