Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection

Stem Cell Research

Songyang Ren¹  Vidhya Kanagavel¹  Aparna Subramanian¹  Joseph Ignatius Irudayam¹  Deisy Contreras¹  Jenieke Allen¹  Vaithilingaraja Arumugaswami¹  Lindsay Spurka²  Quoclinh Nguyen²  Vincent Funari²  Arunachalam Ramaiah³  Kalidas Ramamoorthy⁴  Samuel W. French⁵  Andrew S. Klein⁶ 

[1] Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;Cedars-Sinai Genomics Core, Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA;Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka 560012, India;Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012, India;Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles CA 90095, USA;Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA;

关键词: Pluripotent stem cells;    Endoderm;    Hepatocytes;    Hepatocyte-like cells;    Differentiation;    Interferon;    Innate immunity;    ISG;    Interferon-stimulated genes;   

DOI  :  10.1016/j.scr.2015.08.003

来源: DOAJ

【 摘 要 】

Pluripotent stem cells are being actively studied as a cell source for regenerating damaged liver. For long-term survival of engrafting cells in the body, not only do the cells have to execute liver-specific function but also withstand the physical strains and invading pathogens. The cellular innate immune system orchestrated by the interferon (IFN) pathway provides the first line of defense against pathogens. The objective of this study is to assess the innate immune function as well as to systematically profile the IFN-induced genes during hepatic differentiation of pluripotent stem cells. To address this objective, we derived endodermal cells (day 5 post-differentiation), hepatoblast (day 15) and hepatocyte-like cells (day 21) from human embryonic stem cells (hESCs). Day 5, 15 and 21 cells were stimulated with IFN-α and subjected to IFN pathway analysis. Transcriptome analysis was carried out by RNA sequencing. The results showed that the IFN-α treatment activated STAT–JAK pathway in differentiating cells. Transcriptome analysis indicated stage specific expression of classical and non-classical IFN-stimulated genes (ISGs). Subsequent validation confirmed the expression of novel ISGs including RASGRP3, CLMP and TRANK1 by differentiated hepatic cells upon IFN treatment. Hepatitis C virus replication in hESC-derived hepatic cells induced the expression of ISGs — LAMP3, ETV7, RASGRP3, and TRANK1. The hESC-derived hepatic cells contain intact innate system and can recognize invading pathogens. Besides assessing the tissue-specific functions for cell therapy applications, it may also be important to test the innate immune function of engrafting cells to ensure adequate defense against infections and improve graft survival.

【 授权许可】

Unknown