Abstract
Human liver-derived stem cells (hLD-SCs) have been proposed as a possible resource for stem cell therapy in patients with irreversible liver diseases. However, it is not known whether liver resident hLD-SCs can differentiate toward a hepatic fate better than mesenchymal stem cells (MSCs) obtained from other origins. In this study, we compared the differentiation ability and regeneration potency of hLD-SCs with those of human umbilical cord matrix-derived stem cells (hUC-MSCs) by inducing hepatic differentiation. Undifferentiated hLD-SCs expressed relatively high levels of endoderm-related markers (GATA4 and FOXA1). During directed hepatic differentiation supported by two small molecules (Fasudil and 5-azacytidine), hLD-SCs presented more advanced mitochondrial respiration compared to hUC-MSCs. Moreover, hLD-SCs featured higher numbers of hepatic progenitor cell markers on day 14 of differentiation (CPM and CD133) and matured into hepatocyte-like cells by day 7 through 21 with increased hepatocyte markers (ALB, HNF4A, and AFP). During in vivo cell transplantation, hLD-SCs migrated into the liver of ischemia-reperfusion injury-induced mice within 2 h and relieved liver injury. In the thioacetamide (TAA)-induced liver injury mouse model, transplanted hLD-SCs trafficked into the liver and spontaneously matured into hepatocyte-like cells within 14 days. These results collectively suggest that hLD-SCs hold greater hepatogenic potential, and hepatic differentiation-induced hLD-SCs may be a promising source of stem cells for liver regeneration.
Highlights
Liver replacement therapy or liver transplantation is considered a gold standard for patients with end-stage liver disease [1,2]
Flow cytometry showed that hUC-mesenchymal stromal/stem cells (MSCs) and Human liver-derived stem cells (hLD-SCs) expressed the MSC surface markers, CD90 and CD105, while all Human Umbilical Cord Matrix-Derived Stem Cells (hUC-MSC) and hLD-SCs were negative for the hematopoietic stem cell marker, CD34 (Figure 1B; data from CD34-positive cells are available in Supplementary Figure S1A)
CD90 and CD105 were labeled as mesenchymal stem cell markers
Summary
Liver replacement therapy or liver transplantation is considered a gold standard for patients with end-stage liver disease [1,2]. Recent progress in stem cell technology has provided more expandable sources of liver cells for regenerative medicine and has promoted studies regarding their potential therapeutic application [4]. Embryonic stem cells (ESCs) were considered at one point a possible source for hepatocyte-like cells because of their multipotency. Their use remains restricted in many countries owing to legal issues and ethical concerns [6]. Reprogrammed cells or induced pluripotent stem cells (iPSCs) are widely regarded as the alternative to ESCs; their drawbacks include high cost and safety concerns that constrain their wider use for further clinical applications [7]
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