Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming
- 1Department of Dermatology, UAB Heersink School of Medicine, University of Alabama at Birmingham, AL 35294, USA
Abstract
Fibrotic skin diseases are characterized by persistent fibroblast activation and extracellular matrix remodeling, yet the mechanisms governing fibroblast state transitions remain incompletely understood. Here, we established a human iPSC-derived skin organoid model of fibrosis through chronic TGF-{beta} stimulation. Single-cell RNA sequencing combined with immunofluorescence-based spatial analysis revealed dynamic fibroblast state transitions, spatial reorganization, and expansion of activated fibroblast populations during fibrotic remodeling. Integration with human scleroderma single-cell datasets demonstrated conserved fibroblast states and transcriptional programs between organoids and patient tissues. We further identified broad induction of RUNX2 in the dermal compartment during fibrosis, and RUNX2 depletion attenuated fibrotic marker expression. CUT&RUN profiling revealed RUNX2 occupancy at fibrosis-associated loci, including RUNX1 and LOXL2. Using a machine learning-guided screening approach, we identified F0565-0303, a small molecule that suppressed RUNX2-dependent fibrotic programs in vitro and reduced fibrosis in a bleomycin-induced mouse model. Together, these findings establish human skin organoids as a platform for modeling fibrosis and nominate RUNX2 as a potential therapeutic target.
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BibTeX
@misc{khan2026human,
title = {{Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming}},
author = {J. Khan and S. Mehmood and F. Al Abir and M. Wei and S. Muzaffar and S. Mohiuddin and S. Liu and M. Waseem and J. Akhter and Z. Liu and D. K. Crossman and M. Kamata and J. Y. Chen and C. Raman and C. Elmets and S. Zhang and M. Athar and L. Jin},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.14.751420},
url = {https://www.biorxiv.org/content/10.64898/2026.09.14.751420v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Human skin fibrosis with iPSC-derived organoids reveals RUNX2-mediated fibroblast reprogramming
AU - J. Khan
AU - S. Mehmood
AU - F. Al Abir
AU - M. Wei
AU - S. Muzaffar
AU - S. Mohiuddin
AU - S. Liu
AU - M. Waseem
AU - J. Akhter
AU - Z. Liu
AU - D. K. Crossman
AU - M. Kamata
AU - J. Y. Chen
AU - C. Raman
AU - C. Elmets
AU - S. Zhang
AU - M. Athar
AU - L. Jin
PY - 2026
DA - 2026/09/14
PB - bioRxiv
DO - 10.64898/2026.09.14.751420
UR - https://www.biorxiv.org/content/10.64898/2026.09.14.751420v1
AB - Fibrotic skin diseases are characterized by persistent fibroblast activation and extracellular matrix remodeling, yet the mechanisms governing fibroblast state transitions remain incompletely understood. Here, we established a human iPSC-derived skin organoid model of fibrosis through chronic TGF-{beta} stimulation. Single-cell RNA sequencing combined with immunofluorescence-based spatial analysis revealed dynamic fibroblast state transitions, spatial reorganization, and expansion of activated fibroblast populations during fibrotic remodeling. Integration with human scleroderma single-cell datasets demonstrated conserved fibroblast states and transcriptional programs between organoids and patient tissues. We further identified broad induction of RUNX2 in the dermal compartment during fibrosis, and RUNX2 depletion attenuated fibrotic marker expression. CUT&RUN profiling revealed RUNX2 occupancy at fibrosis-associated loci, including RUNX1 and LOXL2. Using a machine learning-guided screening approach, we identified F0565-0303, a small molecule that suppressed RUNX2-dependent fibrotic programs in vitro and reduced fibrosis in a bleomycin-induced mouse model. Together, these findings establish human skin organoids as a platform for modeling fibrosis and nominate RUNX2 as a potential therapeutic target.
ER -