Nuclear Factor I genes drive chondrogenic cell-fate commitment

Authors

Meulenbelt, I., Mulders, R., Nickel-Maunu, M., van Hoolwerff, M., Mazzini, G., Klomp, L., Meijer, H., Post, J., Ramos, Y.

Abstract

Human induced pluripotent stem cells (hiPSCs) offer a powerful platform to model chondrogenesis and enable regenerative strategies, yet regulation of cell-fate commitment remains elusive. Here, we systematically mapped cell-fate trajectories from 7 time points during a 49-day chondrogenic hiPSC differentiation protocol using single-nucleus multimodal transcriptomic and chromatin accessibility profiling (scRNA-seq and scATAC-seq). Integrative analysis of dynamics revealed branching differentiation trajectories with clear bifurcation points and distinct cell-fates. Notably, the chondrogenic trajectory originated at day 6 as a neurogenic development and branched off at day 21 to a chondrogenic cell-fate. Through transcription factor activity analysis (TFAA) and cis-co-accessibility networks, we found that NFIA and NFIB drove chondrogenic distinction, exhibited in both modalities as directly targeting chondrogenic genes such as COMP, FIBIN, VIM. This was then confirmed by experimental validation as modulation of NFIA expression at this point further enhanced chondrocyte formation. Together, our study provides a high-resolution multimodal atlas of chondrogenic differentiation and identified critical transcriptional regulators that can now be leveraged to implement regenerative cartilage therapies from hiPSCs.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 23 Apr 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.