UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury

Manzano-Nunez, F; Jose Arambul-Anthony, M; Galan Albinana, A; Leal Tassias, A; Acosta Umanzor, C; Borreda Gasco, I; Herrera, A; ... Noon, LA; + view all (2019) Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury. PLOS BIOLOGY , 17 (1) , Article e2006972. 10.1371/journal.pbio.2006972. Green open access

[thumbnail of Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury.pdf]
Preview
Text
Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury.pdf - Published Version

Download (6MB) | Preview

Abstract

Insulin provides important information to tissues about feeding behavior and energy status. Defective insulin signaling is associated with ageing, tissue dysfunction, and impaired wound healing. In the liver, insulin resistance leads to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms integrate insulin signals to coordinate an appropriate injury response or how they are affected by insulin resistance. In this study, we demonstrate that insulin resistance impairs local cellular crosstalk between the fibrotic stroma and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions promote epithelial repair and tissue remodeling. Using insulin-resistant mice deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between stromal niche cells and LPCs during chronic injury. We provide a detailed account of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2- IIIb) expression by the two cell compartments, and we describe an insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on the regulation of IRS2 and FGF7 within the fibrotic stroma and show—using a human coculture system—that IRS2 silencing shifts the equilibrium away from paracrine epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight into the contribution of insulin resistance to the pathogenesis of chronic liver disease and propose IRS2 as a positive regulator of communication between cell types and the transition between phases of stromal to epithelial repair.

Type: Article
Title: Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling during chronic liver injury
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pbio.2006972
Publisher version: https://doi.org/10.1371/journal.pbio.2006972
Language: English
Additional information: © 2019 Manzano-Núñez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10072869
Downloads since deposit
64Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item