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bioRxiv · 10.64898/2026.07.08.735777

Multi-omics profiling links epigenetic and lncRNA changes to early human endochondral ossification priming

Hidalgo Gil, D.·Garcia Garcia, A.·Wolf, F.·Gonzalez Anton, S.·Bosch, S.·Grigoryan, A.·Barbero, A.·Bourgine, P. E.
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Abstract

Differentiation programs remain incompletely understood across stem cell types, including for human bone marrow mesenchymal stromal/stem (BM-MSCs) cells, a heterogenous population orchestrating bone formation and establishing a functional hematopoietic niche in the bone marrow. BM-MSCs form and repair bone through the evolutionarily conserved process of endochondral ossification (EO), initiated by deposition of a transient cartilage template subsequently remodeled into bone and bone marrow tissues. Despite their considerable potential for skeletal regeneration, the early molecular and cellular events underlying BM-MSCs commitment to EO remain elusive. To overcome donor dependent variability in chondrogenic potential that limits mechanistic studies, we here exploit OssiGel as a potent chondro-inductive extracellular matrix offering robust recapitulation of EO by BM-MSCs. Through multi-omics profiling of OssiGel-primed BM-MSCs, we identify rapid chromatin remodeling at chondrogenic loci as concomitant for lineage commitment. The emergence of a chondro-progenitor population is detected as early as 3 days in vivo and correlates with successful EO recapitulation. Mechanistically, we identify LINC02511 as novel enhancer-associated element involved in the onset of EO. We confirm presence of LINC02511 in human skeletal atlases, and its CRISPR-mediated silencing significantly impaired EO. By integrating human tissue engineering strategies with single cell multi-omics profiling, our study provides a framework for deciphering BM-MSCs fate decisions, highlighting the role of enhancer and non-coding elements as key determinants of early lineage specification. These findings advance our understanding of BM-MSCs biology and will prompt their translational exploitation in regenerative medicine.

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Hidalgo Gil, D., Garcia Garcia, A., Wolf, F., Gonzalez Anton, S., Bosch, S., Grigoryan, A., Barbero, A., Bourgine, P. E.. 2026-07-08. Multi-omics profiling links epigenetic and lncRNA changes to early human endochondral ossification priming. https://doi.org/10.64898/2026.07.08.735777

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