{
  "abstract": "Human induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-cFBs) offer a renewable, genetically defined stromal cell source for studying the biology of cardiac fibrosis and of cardiomyocyte-fibroblast crosstalk in the context of development and disease. As cardiac fibroblasts are proliferative cells, the ability to expand iPSC-cFB in culture is attractive given the need for large cell numbers for experiments such as drug screening and tissue engineering efforts. However, potential phenotypic drift during expansion – in particular, the prospect of a premature Fibroblast-to-Myofibroblast-Transition (FMT) is a concern. Here, we investigated how differentiation protocol, mechanical culture history, and serial expansion shape iPSC-cFB phenotype, transforming growth factor-β1 (TGF-β1) 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 expression of α-smooth muscle actin (α-SMA) two markers of FMT. These findings motivated us to study how the rigidity of a poly (dimethyl siloxane) (PDMS; either 15 kPa or 2 MPa) substrate used during initial iPSC-cFB derivation and subsequent expansion impacts both basal phenotype and response to the FMT-inducing growth factor TGF-β. Across iPSC-cFB derived with two independent differentiation protocols, mechanical conditioning produced passage-dependent basal phenotypes and responsiveness to TGF-β. Interestingly, the impact of mechanical pre-conditioning on collective response of iPSC-cFB to TGF-β within “ in vivo -like” 3D cultures was distinct from the impact of this conditioning when the cells were plated to 2D substrates. Together, these findings demonstrate that mechanical culture history shapes iPSC-cFB response capacity and tissue-remodeling behavior without irreversibly fixing fibroblast state. Passage and subsequent microenvironment can attenuate or re-express these history-dependent phenotypes. This study establishes a foundation for using iPSC-cFB for efforts in basic biological discovery and future tissue engineering efforts.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "Huanzhu Jiang",
      "orcid": "0000-0002-0781-896X"
    },
    {
      "name": "Ganesh Malayath",
      "orcid": "0000-0003-3455-7512"
    },
    {
      "name": "Austin Kellogg",
      "orcid": "0009-0001-2216-1206"
    },
    {
      "name": "Nongmaithem Debeni Devi",
      "orcid": "0009-0000-8001-9534"
    },
    {
      "name": "Charlotte Chen",
      "orcid": "0009-0002-3010-2027"
    },
    {
      "name": "Nathaniel Huebsch",
      "orcid": "0000-0002-3329-0214"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7v3vyx1z0qb48.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.20.759862",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1.full",
  "id": "7v3vyx1z0qb48",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Pluripotent Stem Cells Research"
    ]
  ],
  "openalex": "W7223558072",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1.full.pdf",
  "pmcid": "PMC13738644",
  "pmid": "42995954",
  "published": "2026-10-20",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/7v3vyx1z0qb48.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:37Z",
      "native_id": "10.64898/2026.10.20.759862",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.20.759862v1"
    },
    {
      "first_seen": "2026-11-09T12:23:36Z",
      "native_id": "PMC13738644",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.20.759862"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts",
  "title_text": "Mechanical history shapes phenotypic plasticity and fibroblast-autonomous 3D remodeling in iPSC-derived cardiac fibroblasts",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:36Z",
  "url": "https://research.draconitic.com/paper/7v3vyx1z0qb48",
  "venue": "bioRxiv",
  "versions": []
}