HIF1 alpha Regulates Early Metabolic Changes due to Activation of Innate Immunity in Nuclear Reprogramming

• Type of Material: Article
• Authors: Chun Liu, Stanford University; Hongyue Ruan, Chinese Agricultural and Academic Sciences; Farhan Himmati, Stanford University; Ming-Tao Zhao, Stanford University; Christopher C. Chen, Stanford University; Merna Makar, Stanford University; Ian Y. Chen, Stanford University; Karim Sallam, Stanford University; Edward Mocarski, Emory University; Danish Sayed, Rutgers New Jersey Medical School; Nazish Sayed, Stanford University
• Language: English
• Date: 2020-02-11
• Publisher: CELL PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stemcr.2020.01.006
• Title of Journal or Parent Work: STEM CELL REPORTS
• Volume: 14
• Issue: 2
• Start Page: 192
• End Page: 200
• Grant/Funding Information: This work was supported by the NIH K01 HL135455 and AHA-SDG (13SDG17340025) (to N.S.). Go to:
• Keywords: Cell & Tissue Engineering; Life Sciences & Biomedicine; Cell Biology; PLURIPOTENT STEM-CELLS; HUMAN FIBROBLASTS; TRANSDIFFERENTIATION; HYPOXIA; NF-KAPPA-B; Science & Technology
• Research Categories: Biology, Cell; Health Sciences, Immunology

Abstract

Innate immune signaling has recently been shown to play an important role in nuclear reprogramming, by altering the epigenetic landscape and thereby facilitating transcription. However, the mechanisms that link innate immune activation and metabolic regulation in pluripotent stem cells remain poorly defined, particularly with regard to key molecular components. In this study, we show that hypoxia-inducible factor 1α (HIF1α), a central regulator of adaptation to limiting oxygen tension, is an unexpected but crucial regulator of innate immune-mediated nuclear reprogramming. HIF1α is dramatically upregulated as a consequence of Toll-like receptor 3 (TLR3) signaling and is necessary for efficient induction of pluripotency and transdifferentiation. Bioenergetics studies reveal that HIF1α regulates the reconfiguration of innate immune-mediated reprogramming through its well-established role in throwing a glycolytic switch. We believe that results from these studies can help us better understand the influence of immune signaling in tissue regeneration and lead to new therapeutic strategies.