Netrin-1 Acts as a Guardian of Naive Pluripotency in Human Embryonic Stem Cells

Authors

De Neufville, A., Masfaraud, E., Alfeghaly, C., Stoeckl, J. B., Doerflinger, N., Marcy, G., Rognard, C., OSTEIL, P., Lantelme, M., Lavial, F., Chazaud, C., Frohlich, T., Savatier, P., Aksoy, I.

Abstract

We investigated the role of Netrin-1 (NTN1) in human naive pluripotency using complementary loss- and gain-of-function approaches. In primate embryos and human embryonic stem cells (hESCs), Netrin-1 expression is associated with the naive pluripotent state. Disruption of NTN1 had no detectable effect on hESCs maintained on murine embryonic fibroblasts. However, under sub-optimal culture conditions, NTN1-knockout cells exhibited compromised naive pluripotency, which was rescued with feeder cells overexpressing Netrin-1. Netrin-1 overexpression in hESCs accelerated acquisition of the naive state and markedly increased resistance to differentiation. These effects were accompanied by extensive epigenetic remodeling, including H3K27ac and H2K27me3. Proteomic and phospho-proteomic analyses further revealed rapid Netrin-1-dependent alterations in pathways controlling cell adhesion, signaling, and chromatin regulation. Together, these findings extend the role of Netrin-1 beyond its established functions and identify it as a coordinator of extracellular cues, intracellular signaling, and nuclear regulatory mechanisms that support human naive pluripotency.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 17 Jul 2026.

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