--- title: "Hepatic stellate cells-stiff env myofibroblast differentiatn | Sutter Health" description: "Hepatic stellate cells require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate." url: "https://www.sutterhealth.org/research/publications/hsc-stiff-env-myofibroblastic-differentiatn-1055312899" --- 1. [Home](https://www.sutterhealth.org/) / 2. [Research](https://www.sutterhealth.org/research) / 3. [Research publications](https://www.sutterhealth.org/research/publications) / 4. Hepatic stellate cells-stiff env myofibroblast differentiatn # Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Olsen AL, Bloomer SA, Chan EP, Gaça MD, Georges PC, Sackey B, Uemura M, Janmey PA, & Wells RG. _Am J Physiol Gastrointest Liver Physiol. 301(1):G110-8. doi: 10.1152/ajpgi.00412.2010. Epub 2011 Apr 28._ 2011-07-01 ## Abstract The myofibroblastic differentiation of hepatic stellate cells (HSC) is a critical event in liver fibrosis and is part of the final common pathway to cirrhosis in chronic liver disease from all causes. The molecular mechanisms driving HSC differentiation are not fully understood. Because macroscopic tissue stiffening is a feature of fibrotic disease, we hypothesized that mechanical properties of the underlying matrix are a principal determinant of HSC activation. Primary rat HSC were cultured on inert polyacrylamide supports of variable but precisely defined shear modulus (stiffness) coated with different extracellular matrix proteins or poly-L-lysine. HSC differentiation was determined by cell morphology, immunofluorescence staining, and gene expression. HSC became progressively myofibroblastic as substrate stiffness increased on all coating matrices, including Matrigel. The degree rather than speed of HSC activation correlated with substrate stiffness, with cells cultured on supports of intermediate stiffness adopting stable intermediate phenotypes. Quiescent cells on soft supports were able to undergo myofibroblastic differentiation with exposure to stiff supports. Stiffness-dependent differentiation required adhesion to matrix proteins and the generation of mechanical tension. Transforming growth factor-β treatment enhanced differentiation on stiff supports, but was not required. HSC differentiate to myofibroblasts in vitro primarily as a function of the physical rather than the chemical properties of the substrate. HSC require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate. These findings suggest that alterations in liver stiffness are a key factor driving the progression of fibrosis. [PubMed abstract](http://www.ncbi.nlm.nih.gov/pubmed/21527725) ## Research topics - [Liver Diseases and Transplant](https://www.sutterhealth.org/research-search-results?query=%22%5C%22Liver+Diseases+and+Transplant%5C%22%22) ## Related publications [View all publications](https://www.sutterhealth.org/research-search-results?verticalKey=research_publication) - Publication ### [Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture.](https://www.sutterhealth.org/research/publications/tgf-beta-regulate-fibroblast-activation-culture-1055312985) Li Z, Dranoff JA, Chan EP, Uemura M, Sévigny J, Wells RG. Hepatology. 46(4):1246-56. 2007 Oct 01 - Publication ### [Today's hepatic stellate cells: not your father's sternzellen.](https://www.sutterhealth.org/research/publications/hepatic-stellate-cells-not-fathers-sternzellen-1055312891) Chan EP, Wells RG. Hepatology. 45(5):1326-7. 2007 May 01 - Publication ### [Factors associated with prevalence and treatment of primary biliary cholangitis in United States health systems.](https://www.sutterhealth.org/research/publications/prevalence-tx-biliary-cholangitis-in-us-1055312312) Lu M, Li J, Haller IV, Romanelli RJ, VanWormer JJ, Rodriguez CV, Raebel MA, Boscarino JA, Schmidt MA, Daida YG, Sahota A, Vincent J, Bowlus CL, Lindor K, Rupp LB, Gordon SC; FOLD Investigators. Clin Gastroenterol Hepatol. pii: S1542-3565(17)31243-0. doi: 10.1016/j.cgh.2017.10.018. \[Epub ahead of print\] 2017 Oct 21 - Publication ### [Ursodeoxycholic acid treatment preferentially improves overall survival among African Americans with primary biliary cholangitis.](https://www.sutterhealth.org/research/publications/ursodeoxycholic-acid-treatment-for-biliary-cholangitis-1055312732) Gordon SC, Wu KH, Lindor K, Bowlus CL, Rodriguez CV, Anderson H, Boscarino JA, Trudeau S, Rupp LB, Haller IV, Romanelli RJ, VanWormer JJ, Schmidt MA, Daida YG, Sahota A, Vincent J, Zhang T, Li J, Lu M; FOLD Investigators. Am J Gastroenterol. 2020 Jan 27. doi: 10.14309/ajg.0000000000000512. \[Epub ahead of print\] 2020 Jan 27 - Publication ### [Increasing prevalence of primary biliary cholangitis and reduced mortality with treatment.](https://www.sutterhealth.org/research/publications/prevalence-and-tx-of-primary-biliary-cholangitis-in-us-1055312359) Lu M, Zhou Y, Haller IV, Romanelli RJ, VanWormer JJ, Rodriguez CV, Anderson H, Boscarino JA, Schmidt MA, Daida YG, Sahota A, Vincent J, Bowlus CL, Lindor K, Zhang T, Trudeau S, Li J, Rupp LB, Gordon SC; FOLD Investigators. Clin Gastroenterol Hepatol. pii: S1542-3565(17)31529-X. doi: 10.1016/j.cgh.2017.12.033. \[Epub ahead of print\] 2017 Dec 22 [View all publications](https://www.sutterhealth.org/research-search-results?verticalKey=research_publication) ```json {"@context":"https://schema.org","@type":"MedicalOrganization","name":"Sutter Health","@id":"https://www.sutterhealth.org/#medicalorganization","url":"https://www.sutterhealth.org","logo":"https://www.sutterhealth.org/static/images/sutter-health-logo.svg","address":{"@type":"PostalAddress","streetAddress":"2200 River Plaza Drive","addressLocality":"Sacramento","addressRegion":"CA","postalCode":"95833","addressCountry":"US"},"areaServed":{"@type":"AdministrativeArea","name":"California"},"sameAs":["https://www.facebook.com/SutterHealth","https://www.instagram.com/sutterhealth/","https://x.com/SutterHealth","https://www.youtube.com/sutterhealth","https://www.linkedin.com/company/sutter-health","https://en.wikipedia.org/wiki/Sutter_Health"]} ``` ```json {"@context":"https://schema.org","@type":"BreadcrumbList","@id":"https://www.sutterhealth.org/research/publications/hsc-stiff-env-myofibroblastic-differentiatn-1055312899#breadcrumblist","itemListElement":[{"@type":"ListItem","position":1,"name":"Home","item":"https://www.sutterhealth.org/"},{"@type":"ListItem","position":2,"name":"Research","item":"https://www.sutterhealth.org/research"},{"@type":"ListItem","position":3,"name":"Research publications","item":"https://www.sutterhealth.org/research/publications"},{"@type":"ListItem","position":4,"name":"Hepatic stellate cells-stiff env myofibroblast differentiatn"}]} ``` ```json {"@context":"https://schema.org","@type":"MedicalScholarlyArticle","@id":"https://www.sutterhealth.org/research/publications/hsc-stiff-env-myofibroblastic-differentiatn-1055312899#medicalscholarlyarticle","name":"Hepatic stellate cells require a stiff environment for myofibroblastic differentiation.","headline":"Hepatic stellate cells-stiff env myofibroblast differentiatn","abstract":"The myofibroblastic differentiation of hepatic stellate cells (HSC) is a critical event in liver fibrosis and is part of the final common pathway to cirrhosis in chronic liver disease from all causes. The molecular mechanisms driving HSC differentiation are not fully understood. Because macroscopic tissue stiffening is a feature of fibrotic disease, we hypothesized that mechanical properties of the underlying matrix are a principal determinant of HSC activation. Primary rat HSC were cultured on inert polyacrylamide supports of variable but precisely defined shear modulus (stiffness) coated with different extracellular matrix proteins or poly-L-lysine. HSC differentiation was determined by cell morphology, immunofluorescence staining, and gene expression. HSC became progressively myofibroblastic as substrate stiffness increased on all coating matrices, including Matrigel. The degree rather than speed of HSC activation correlated with substrate stiffness, with cells cultured on supports of intermediate stiffness adopting stable intermediate phenotypes. Quiescent cells on soft supports were able to undergo myofibroblastic differentiation with exposure to stiff supports. Stiffness-dependent differentiation required adhesion to matrix proteins and the generation of mechanical tension. Transforming growth factor-β treatment enhanced differentiation on stiff supports, but was not required. HSC differentiate to myofibroblasts in vitro primarily as a function of the physical rather than the chemical properties of the substrate. HSC require a mechanically stiff substrate, with adhesion to matrix proteins and the generation of mechanical tension, to differentiate. 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