Stiffness is associated with hepatic stellate cell heterogeneity during liver fibrosis

Enis Kostallari, Bo Wei, Delphine Sicard, Jiahui Li, Shawna A. Cooper, Jinhang Gao, Mrunal Dehankar, Ying Li, Sheng Cao, Meng Yin, Daniel J. Tschumperlin, Vijay H. Shah

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)G234-G246
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number2
StatePublished - Feb 2022


  • Atomic force microscopy
  • Fibrosis
  • Magnetic resonance elastography
  • Single-cell RNA sequencing
  • Stiffness

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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