Robust Expansion and Functional Maturation of Human Hepatoblasts by Chemical Strategy
Abstract Background: Chemically strategies to generate hepatic cells from human pluripotent stem cells (hPSCs) for the potential clinical application have been improved. However, producing high quality and large quantities of hepatic cells remain challenging, especially in terms of step-wise efficacy and cost-effective production requires more improvements. Methods: Here, we systematically evaluated chemical compounds for hepatoblasts (HBs) expansion and maturation to establish a robust, cost-effective and reproducible methodology for self-renewal HBs and functional hepatocyte-like cells (HLCs) production. Results: The established chemical cocktail could enable HBs to proliferate nearly 3000 folds within 3 weeks with preserved bipotency. Moreover, those expanded HBs could be further efficiently differentiated into homogenous HLCs displayed typical morphologic and functionality as mature hepatocytes, including hepatocyte identity markers expression and key functional activities such as cytochrome P450 metabolism activities and urea secretion. Importantly, the transplanted HBs in injured liver of immune-defect mice differentiated as hepatocytes, engraft and repopulate in the injured loci of the recipient liver. Conclusion: Together, this chemical compound based HLCs generation method presents an efficient and cost-effective platform for the large-scale production of functional human hepatic cells for cell-based therapy and drug discovery application.