Reprogramming Dedifferentiation Regulatory Networks Preserves Human Chondrocyte Phenotypes.

Authors

Ellen Y Zhang, Sang Hyun Lee, Yu-Chung Liu, Yuna Heo, Hannah H Kim, Dong Hwa Kim, Tyler E Blanch, Jaeun Jung, Claudia Loebel, Melike Lakadamyali, Robert L Mauck, Inkyung Jung, Su Chin Heo

Published in

bioRxiv : the preprint server for biology. May 13, 2026. Epub May 13, 2026.

Abstract

Chondrocyte-based cartilage repair strategies such as autologous chondrocyte implantation (ACI) require extensive in vitro expansion to obtain clinically relevant cell numbers. However, this expansion step progressively drives chondrocyte dedifferentiation, reducing matrix-forming capacity and contributing to variable repair outcomes. To better understand this process, we used single-nucleus multiome profiling (snRNA-Seq + snATAC-Seq) to define the transcriptional and chromatin accessibility programs underlying human chondrocyte dedifferentiation during expansion. Multiome integration across passages revealed a continuous dedifferentiation trajectory accompanied by coordinated remodeling of gene expression and chromatin accessibility, identifying chromatin destabilization as an early regulatory event during phenotype loss. Guided by these regulatory signatures, we screened available small-molecule inhibitors targeting candidate pathways and found that Fludarabine most consistently preserved chondrocyte identity during early expansion. Fludarabine was associated with suppression of STAT1-related programs and early stabilization of the chromatin landscape prior to broader transcriptional recovery. Functionally, treated cells demonstrated enhanced matrix-forming capacity in chondrogenic pellet culture and significantly increased nascent protein synthesis in 3D hydrogel culture, with biosynthetic output approaching unexpanded controls by day 21. Together, these findings identify chromatin stability as a key regulatory determinant of expansion-associated chondrocyte dedifferentiation and establish a pharmacologic strategy to preserve chondrocyte functional potency during cell manufacturing for cartilage repair.

PMID:
42182122
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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