---
title: "Mechanical culture history changes iPSC-derived cardiac fibroblast phenotype and 3D remodeling"
id: "biorxiv-4-mechanical-history-shapes-phenotypic-plasticity-and-fibroblast-autonomous-3d"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-4-mechanical-history-shapes-phenotypic-plasticity-and-fibroblast-autonomous-3d"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1?rss=1"
published_at: "2026-10-25T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Mechanical culture history changes iPSC-derived cardiac fibroblast phenotype and 3D remodeling
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-4-mechanical-history-shapes-phenotypic-plasticity-and-fibroblast-autonomous-3d
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1?rss=1)
- **Published At:** 2026-10-25T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The study examined how differentiation protocol, mechanical culture history, and serial expansion affect human **iPSC-cFBs** phenotypes, responsiveness to **TGF-beta1**, and fibroblast-driven remodeling in three-dimensional tissues. - Investigators expanded iPSC-cFBs on tissue-culture polystyrene (TCP) and observed passage-associated increases in projected cell area and **alpha-SMA** expression—markers associated with fibroblast-to-myofibroblast transition (FMT). - The team compared expansion on poly(dimethylsiloxane) (PDMS) substrates of two stiffnesses (15 kPa and 2 MPa) and found that mechanical history shaped basal phenotypes in a passage-dependent manner across two independent differentiation protocols. - Data indicated that mechanical history altered collective responses to **TGF-beta1**, and that these responses in three-dimensional cultures did not mirror those measured after replating cells onto two-dimensional substrates. - Authors reported that mechanical history modulates iPSC-cFB responsiveness and tissue-remodeling behavior without irreversibly fixing fibroblast state; later passage and microenvironmental changes can attenuate or re-express history-dependent phenotypes. - The preprint supports the utility of iPSC-cFBs for basic research and tissue engineering applications but is a preprint and has not undergone peer review. - The source did not report specific culture timelines, detailed quantitative measures, or exact experimental protocols in the abstract; readers should consult the full manuscript and supplementary materials for methods and numeric data.
## Clinical Analysis & Structured Key Points
Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts | bioRxiv Skip to main content New Results Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts View ORCID Profile Huanzhu Jiang , View ORCID Profile Ganesh Malayath , View ORCID Profile Austin Kellogg , View ORCID Profile Nongmaithem Debeni Devi , View ORCID Profile Charlotte Chen , View ORCID Profile Nathaniel Huebsch doi: https://doi.org/10.64898/2026.10.20.759862 Huanzhu Jiang 1 Washington University in St. Louis; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Huanzhu Jiang Ganesh Malayath 2 Washington University in St Louis; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Ganesh Malayath Austin Kellogg 1 Washington University in St. Louis; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Austin Kellogg Nongmaithem Debeni Devi 1 Washington University in St. Louis; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nongmaithem Debeni Devi Charlotte Chen 1 Washington University in St. Louis; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Charlotte Chen Nathaniel Huebsch 3 Washington University in Saint Louis Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Nathaniel Huebsch For correspondence: nhuebsch{at}wustl.edu Abstract Info/History Metrics Supplementary material Preview PDF Abstract Human induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-cFBs) offer a renewable, genetically defined stromal cell source for studying cardiac fibrosis and cardiomyocyte-fibroblast crosstalk during development and disease. Because cardiac fibroblasts are proliferative, expansion of iPSC-cFBs in culture is attractive for applications requiring large cell numbers, including drug screening and tissue engineering. However, phenotypic drift during expansion, particularly premature fibroblast-to-myofibroblast transition (FMT), remains a concern. Here, we investigated how differentiation protocol, mechanical culture history, and serial expansion shape iPSC-cFB phenotype, transforming growth factor beta 1 (TGF-beta1) responsiveness, and fibroblast-autonomous remodeling in three-dimensional (3D) tissues. Initial studies of iPSC-cFBs expanded on conventional tissue-culture polystyrene (TCP) revealed passage-associated increases in projected cell area and alpha-smooth muscle actin (alpha-SMA) expression, two markers associated with FMT. These findings prompted us to examine how the stiffness of poly(dimethylsiloxane) (PDMS) substrates (15 kPa or 2 MPa) used during iPSC-cFB derivation and expansion influences basal phenotype and response to TGF-beta1. Across two independent differentiation protocols, mechanical culture history shaped passage-dependent basal phenotypes and responses to TGF-beta1. Notably, its effects on collective TGF-beta1 responses in three-dimensional cultures differed from those observed after replating cells onto two-dimensional substrates. Together, these findings demonstrate that mechanical culture history modulates iPSC-cFB responsiveness and tissue-remodeling behavior without irreversibly determining fibroblast state. Subsequent passage and microenvironmental conditions can attenuate or re-express these history-dependent phenotypes. This work supports the use of iPSC-cFBs in basic biological discovery and future tissue engineering applications. Competing Interest Statement The authors have declared no competing interest. Funder Information Declared National Heart, Lung, and Blood Institute , R01HL159094 , R01HL170079 U.S. National Science Foundation, https://ror.org/021nxhr62 , 2338931 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted October 25, 2026. Download PDF Supplementary Material Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts Huanzhu Jiang , Ganesh Malayath , Austin Kellogg , Nongmaithem Debeni Devi , Charlotte Chen , Nathaniel Huebsch bioRxiv 2026.10.20.759862; doi: https://doi.org/10.64898/2026.10.20.759862 Share This Article: Copy Citation Tools Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts Huanzhu Jiang , Ganesh Malayath , Austin Kellogg , Nongmaithem Debeni Devi , Charlotte Chen , Nathaniel Huebsch bioRxiv 2026.10.20.759862; doi: https://doi.org/10.64898/2026.10.20.759862 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8164) Biochemistry (19027) Bioengineering (15171) Bioinformatics (45372) Biophysics (22958) Cancer Biology (20120) Cell Biology (27314) Clinical Trials (138) Developmental Biology (14149) Ecology (21402) Epidemiology (2067) Evolutionary Biology (25816) Genetics (16349) Genomics (23848) Immunology (19033) Microbiology (43209) Molecular Biology (18346) Neuroscience (95152) Paleontology (714) Pathology (3036) Pharmacology and Toxicology (5201) Physiology (8287) Plant Biology (16274) Scientific Communication and Education (2116) Synthetic Biology (4647) Systems Biology (10389) Zoology (2427)
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