Abstract
Induced hepatic stem cells (iHepSCs) have great potential as donors for liver cell therapy due to their self-renewal and bipotential differentiation properties. However, the efficiency of bidifferentiation and repopulation efficiency of iHepSCs is relatively low. Recent evidence shows that physiological hypoxia, a vital factor within stem cell “niche” microenvironment, plays key roles in regulating tissue stem cell biological behaviors including proliferation and differentiation. In this study, we found that physiological hypoxia (10% O2) enhanced the stemness properties and promoted the proliferation ability of iHepSCs by accelerating G1/S transition via p53-p21 signaling pathway. In addition, short-term hypoxia preconditioning improved the efficiency of hepatic differentiation of iHepSCs, and long-term hypoxia promoted cholangiocytic differentiation but inhibited hepatic differentiation of iHepSCs. These results demonstrated the potential effects of hypoxia on stemness preservation, proliferation, and bidifferentiation of iHepSCs and promising perspective to explore appropriate culture conditions for therapeutic stem cells.
Highlights
Induced hepatic stem cells are lineagereprogrammed cells originating from murine embryonic fibroblasts via two confirmed transcription factors Hnf1β, Foxa3
Recent evidence shows that changes in the microenvironment of specific tissue stem cells residing in stem cell “niche,” including the oxygen concentration in Oxidative Medicine and Cellular Longevity particular, play key roles in regulating their biological behaviors [3]
Knowing that low oxygen tension preserved stemness of bone mesenchymal stem cells (BMSCs), adipose-derived MSCs (ADMSCs), and multiple cancer cells [17,18,19], we predicted that hypoxia may preserve the stem properties of Induced hepatic stem cells (iHepSCs)
Summary
Induced hepatic stem cells (iHepSCs) are lineagereprogrammed cells originating from murine embryonic fibroblasts via two confirmed transcription factors Hnf1β, Foxa. Our previous work [1] showed that iHepSCs expressed hepatic stem cell markers CK19, EpCAM, Sox, and Lgr and possessed the capability of bipotentially differentiating to mature hepatocytes and cholangiocytes under certain conditions in vitro. The oxygen concentration is one of the most important regulators for organ development and tissue construction, with a well-established steering effects, on overall cell metabolism, proliferation, and differentiation [2]. Recent evidence shows that changes in the microenvironment of specific tissue stem cells residing in stem cell “niche,” including the oxygen concentration in Oxidative Medicine and Cellular Longevity particular, play key roles in regulating their biological behaviors [3].
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