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

Joseph Ignatius Irudayam; Deisy Contreras; Lindsay Spurka; Aparna Subramanian; Jenieke Allen; Songyang Ren; Vidhya Kanagavel; Quoclinh Nguyen; Arunachalam Ramaiah; Kalidas Ramamoorthy; Samuel W. French; Andrew S. Klein; Vincent Funari; Vaithilingaraja Arumugaswami

doi:10.1016/j.scr.2015.08.003

Stem Cell Research (Sep 2015)

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

Joseph Ignatius Irudayam,
Deisy Contreras,
Lindsay Spurka,
Aparna Subramanian,
Jenieke Allen,
Songyang Ren,
Vidhya Kanagavel,
Quoclinh Nguyen,
Arunachalam Ramaiah,
Kalidas Ramamoorthy,
Samuel W. French,
Andrew S. Klein,
Vincent Funari,
Vaithilingaraja Arumugaswami

Affiliations

Joseph Ignatius Irudayam: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Deisy Contreras: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Lindsay Spurka: Cedars-Sinai Genomics Core, Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA
Aparna Subramanian: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Jenieke Allen: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Songyang Ren: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Vidhya Kanagavel: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Quoclinh Nguyen: Cedars-Sinai Genomics Core, Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA
Arunachalam Ramaiah: Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, Karnataka 560012, India
Kalidas Ramamoorthy: Department of Biotechnology, Manonmaniam Sundaranar University, Tirunelveli, Tamil Nadu 627012, India
Samuel W. French: Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles CA 90095, USA
Andrew S. Klein: Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Vincent Funari: Cedars-Sinai Genomics Core, Medical Genetics Institute, Cedars-Sinai Medical Center Los Angeles, CA 90048, USA
Vaithilingaraja Arumugaswami: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

DOI: https://doi.org/10.1016/j.scr.2015.08.003
Journal volume & issue: Vol. 15, no. 2
pp. 354 – 364

Abstract

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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.

Published in Stem Cell Research

ISSN: 1873-5061 (Print); 1876-7753 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: https://www.journals.elsevier.com/stem-cell-research

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