HIF1α Regulates Early Metabolic Changes due to Activation of Innate Immunity in Nuclear Reprogramming

• Main Authors: Chun Liu, Hongyue Ruan, Farhan Himmati, Ming-Tao Zhao, Christopher C. Chen, Merna Makar, Ian Y. Chen, Karim Sallam, Edward S. Mocarski, Danish Sayed, Nazish Sayed
• Format: Article
• Language: English
• Published: Elsevier 2020-02-01
• Series: Stem Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213671120300278

Summary: 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. : In this article, Sayed and colleagues have identified HIF1α, a central regulator of adaptation to limiting oxygen tension, as an unexpected but crucial regulator of innate immune-mediated nuclear reprogramming. By studying the potential to reprogram via the activation of the innate immune system, we intend to understand the dormant regenerative machinery in humans. Keywords: innate immunity, nuclear reprogramming, transdifferentiation, hypoxia-inducible factor 1, glycolysis, iPSCs, endothelial cells, regeneration, metabolism, chromatin