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Received Oct 10, 2017; Accepted Dec 24, 2017
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
1. Introduction
Induced hepatic stem cells (iHepSCs) are lineage-reprogrammed cells originating from murine embryonic fibroblasts via two confirmed transcription factors Hnf1β, Foxa3. Our previous work [1] showed that iHepSCs expressed hepatic stem cell markers CK19, EpCAM, Sox9, and Lgr5 and possessed the capability of bipotentially differentiating to mature hepatocytes and cholangiocytes under certain conditions in vitro. In addition, iHepSCs could engraft and save the liver in a mouse model of hereditary tyrosinemia type I (HT1) and also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury, showing great perspective for cell therapy of chronic liver injury. However, the induction efficiency of both hepatic and cholangiocytic differentiation and repopulation efficiency of iHepSCs are relatively low.
Physiological hypoxia refers to a condition where the oxygen concentration inside the human body is significantly lower than that in the atmosphere. 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 particular, play key roles in regulating their biological behaviors [3]. Cells are normally cultured in vitro in the presence of 5% CO2 and about 20% oxygen. However, the natural cell microenvironment contains a much lower oxygen concentration ranging from 12% in arterial blood to 1–7% in a variety of other tissues [4]. Studies in recent years have provided evidence regarding the negative influence of the ambient O2 concentration on stem cells, causing longer population doubling time and DNA damage [5, 6]. In contrast, 5% O2 hypoxia enhanced the growth of dental pulp stem cells (DPSCs) and the stem property of stem cells [7]. Notably, low O2 tension promoted the survival of neural crest cells and hematopoietic stem cells and maintained pluripotency of human embryonic stem cells (ESCs) [8, 9]. Hypoxia also promoted reprogramming mouse embryonic fibroblasts into induced...