期刊
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
卷 322, 期 2, 页码 G234-G246出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00254.2021
关键词
atomic force microscopy; fibrosis; magnetic resonance elastography; single-cell RNA sequencing; stiffness
资金
- American Association for the Study of Liver Diseases Pinnacle Research Award
- Mayo Clinic Center for Cell Signaling in Gastroenterology Pilot/Feasibility Award [P30DK084567]
- National Institutes of Health [UH2/3 AA026887, R01 EB017197, R01 HL133320-1, R01 HL092961, R37 AA021171-06, R01 DK59615-16]
The wound-healing response in liver increases stiffness, which in turn amplifies fibrogenesis. This study reveals heterogeneous distribution of stiffness in fibrotic liver at macroscopic and microscopic levels and its impact on hepatic stellate cell heterogeneity. Stiffness in high-density extracellular matrix areas is mainly responsible for high liver stiffness. Moreover, a specific protein, FHL2, is found to be upregulated in a stiffness-sensitive subpopulation of hepatic stellate cells, promoting extracellular matrix production.
The fibrogenic wound-healing response in liver increases stiffness. Stiffness mechanotransduction, in turn, amplifies fibrogenesis. Here, we aimed to understand the distribution of stiffness in fibrotic liver, how it impacts hepatic stellate cell (HSC) heterogeneity, and identify mechanisms by which stiffness amplifies fibrogenic responses. Magnetic resonance elastography and atomic force microscopy demonstrated a heterogeneous distribution of liver stiffness at macroscopic and microscopic levels, respectively, in a carbon tetrachloride (CCl4) mouse model of liver fibrosis as compared with controls. High stiffness was mainly attributed to extracellular matrix dense areas. To identify a stiffness-sensitive HSC subpopulation, we performed single-cell RNA sequencing (scRNA-seq) on primary HSCs derived from healthy versus CCl4-treated mice. A subcluster of HSCs was matrix -associated with the most upregulated pathway in this subpopulation being focal adhesion signaling, including a specific protein termed four and a half LIM domains protein 2 (FHL2). In vitro, FHL2 expression was increased in primary human HSCs cultured on stiff matrix as compared with HSCs on soft matrix. Moreover, FHL2 knockdown inhibited fibronectin and collagen 1 expression, whereas its overexpression promoted matrix production. In summary, we demonstrate stiffness heterogeneity at the whole organ, lobular, and cellular level, which drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways. NEW & NOTEWORTHY The fibrogenic wound-healing response in liver increases stiffness. Here, macro and microheterogeneity of liver stiffness correlate with HSC heterogeneity in a hepatic fibrosis mouse model. Fibrogenic HSCs localized in stiff collagen high areas upregulate the expression of focal adhesion molecule FHL2, which, in turn, promotes extracellular matrix protein expression. These results demonstrate that stiffness heterogeneity at the whole organ, lobular, and cellular level drives an amplification loop of fibrogenesis through specific focal adhesion molecular pathways.
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