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

Irudayam, Joseph Ignatius and Contreras, Deisy and Spurka, Lindsay and Subramanian, Aparna and Allen, Jenieke and Ren, Songyang and Kanagavel, Vidhya and Nguyen, Quoclinh and Ramaiah, Arunachalam and Ramamoorthy, Kalidas and French, Samuel W and Klein, Andrew S and Funari, Vincent and Arumugaswami, Vaithilingaraja (2015) Characterization of type I interferon pathway during hepatic differentiation of human pluripotent stem cells and hepatitis C virus infection. In: STEM CELL RESEARCH, 15 (2). pp. 354-364.

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Abstract

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-alpha and subjected to IFN pathway analysis. Transcriptome analysis was carried out by RNA sequencing. The results showed that the IFN-alpha 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. (C) 2015 The Authors. Published by Elsevier B.V.

Item Type:	Journal Article
Publication:	STEM CELL RESEARCH
Publisher:	ELSEVIER SCIENCE BV
Additional Information:	Copy right for this article belongs to the ELSEVIER SCIENCE BV, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS
Keywords:	Pluripotent stem cells; Endoderm; Hepatocytes; Hepatocyte-like cells; Differentiation; Interferon; Innate immunity; ISG; Interferon-stimulated genes
Department/Centre:	Division of Biological Sciences > Centre for Infectious Disease Research
Date Deposited:	02 Jan 2016 10:13
Last Modified:	02 Jan 2016 10:13
URI:	http://eprints.iisc.ac.in/id/eprint/53021

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