Current strategies to generate mature human induced pluripotent stem cells derived cholangiocytes and future applications

Abstract

ABSTRACT. Stem cell research has significantly evolved over the last few years, allowing the differentiation of pluripotent cells into almost any kind of lineage possible. Studies that focus on the liver have considerably taken a leap into this novel technology, and hepatocyte-like cells are being generated that are close to resembling actual hepatocytes both genotypically and phenotypically. The potential of this extends from disease models to bioengineering, and even also innovative therapies for end-stage liver disease. Nonetheless, too few attention has been given to the non-parenchymal cells which are also fundamental for normal liver function. This includes cholangiocytes, the cells of the biliary epithelium, without whose role in bile modification and metabolism would impair hepatocyte survival. Such can be observed in diseases that target them, so called cholangiopathies, for which there is much yet to study so as to improve therapeutical options. Protocols that describe the induction of human induced pluripotent stem cells into cholangiocytes are scarce, although progress is being achieved in this area as well. In order to give the current view on this emerging research field, and in hopes to motivate further advances, we present here a review on the known differentiation strategies with sight into future applications.

Liver Illness and Psoriatic Patients

“…IL-6 is a pleiotropic cytokines involved in chronic inflammation and liver carcinogenesis and found to be related to hepatic function and tumor progression and determine HCC patient survival [ 89 ]. TNF- α playing an inflammatory role in regulating hepatocyte proliferation and regeneration and its overexpression is related to tumor progression because of released to nonparenchymal cells in HCC [ 90 ]. Vascular-endothelial growth factor is highly expressed in HCC as well, a typical hypervascular tumor [ 91 ].…”

Tissue-Engineered Bile Ducts for Disease Modeling and Therapy

“…[13][14][15] Cholangiocytes and cholangiocytebased organoids derived from induced pluripotent stem cells (iPSCs) are advancements in the field of liver cell culture and the emerging field of tissue engineering, specifically bile duct engineering, offering a variety of choices regarding cell source and desired differentiated cell type. [16][17][18] However, heterogeneity of morphological features, functional assays, and marker-expression of stem cell-derived cholangiocytes is still observed in vitro. In this review, we focus on strategies of human cholangiocyte differentiation and the heterogeneity of obtained cell types.…”

Large-scale Generation of Functional and Transplantable Hepatocytes and Cholangiocytes from Human Endoderm Stem Cells

“…In addition, drug discovery and toxicological research are limited by the availability of functional hepatic cells and the lack of relevant pathological models that incorporate the major liver cell types. Therefore, generating functional and transplantable hepatic cells at large scales to meet the ever-increasing therapeutic and pharmaceutical demand is a major challenge that must be confronted (Cervantes-Alvarez et al, 2017;Gerbal-Chaloin et al, 2014).…”

“…Protocols using various stem or adult cells as starting material have been developed to generate or expand hepatic cells in vitro (Ogawa et al, 2013(Ogawa et al, , 2015Sampaziotis et al, 2015;Si-Tayeb et al, 2010b;Touboul et al, 2016;Vosough et al, 2013;Xiang et al, 2019;Zhang et al, 2018a). Significant effort has been made in the past decade to direct differentiation of human pluripotent stem cells (hPSCs) into hepatocytes or cholangiocytes (Cervantes-Alvarez et al, 2017;Gerbal-Chaloin et al, 2014). Most protocols were designed to recapitulate the in vivo developmental processes that involve sequential progression through definitive endoderm (DE), hepatic endoderm (HE), HBs, and, eventually, mature hepatic lineages by modulating the stagespecific cell signaling pathways (Cervantes-Alvarez et al, 2017;Gerbal-Chaloin et al, 2014).…”