Research Paper Volume 10, Issue 12 pp 3713—3735
Reduced production of laminin by hepatic stellate cells contributes to impairment in oval cell response to liver injury in aged mice
- 1 Department of General Surgery, The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China
- 2 Department of General Surgery, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
- 3 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
Received: September 12, 2018 Accepted: November 15, 2018 Published: December 4, 2018
https://doi.org/10.18632/aging.101665How to Cite
Copyright: Qian et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Aged liver is usually impaired in response to hepatic injury. Tissue-specific stem cells participate in the repair of tissue injury. However, how oval cells (OCs) respond to injury and how the process is regulated by tissue microenvironment in aged mice have not been fully understood. In this study, taking advantage of well-established murine OC activation model, we demonstrated that OCs were less activated upon injury in aged mice and the impairment was mainly attributed to dysfunction in their niche. Through analyzing global gene expression, we found that the genes differentially expressed in damaged young and aged mouse liver tissues were predominantly those required for the formation and remodeling of extracellular matrix. As one of the most important extracellular matrix components in the OC niche, laminin was shown to promote the proliferation of OCs. Not surprisingly, laminin was downregulated with aging. Consistent with the downregulation of genes encoding DNA-dependent protein kinase (DNA-PK) proteins in aged hepatic stellate cells (HSCs), inhibition of DNA-PK also led to reduced expression of laminin in HSCs. Moreover, impairment in OC activation caused by less supporting from DNA-damaged HSCs could be rescued by laminin. This study reveals a new cellular mechanism underlying impaired OCs functionality during aging.
Abbreviations
OCs: oval cells; DDC: 3,5-diethoxycarbonyl-1,4-dihydrocollidine; ECM: extracellular matrix; HSCs: hepatic stellate cells; α-SMA: α-smooth muscle actin; DNA-PK: DNA-dependent protein kinase; NPCs: nonparenchymal cells; IGF: insulin growth factor; GH: growth hormone; GDF: growth differentiation factor; DSBs: double strain breaks; HR: homologous recombination; NHEJ: nonhomologous end joining; DMNB: 4,5-Dimethoxy-2-nitrobenzaldehyde; MFI: mean fluorescence intensity.