Hypoxia-induced conversion of sensory Schwann cells into repair cells is regulated by HDAC8

Nadège Hertzog, Mert Duman, Maëlle Bochud, Valérie Brügger-Verdon, Maren Gerhards, Felicia Schön, Franka Dorndecker, Dies Meijer, Robert Fledrich, Ruth Stassart, Devanarayanan Siva Sankar, Jörn Dengjel, Sofía Raigón López and Claire Jacob ()
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Nadège Hertzog: Johannes Gutenberg University Mainz
Mert Duman: Johannes Gutenberg University Mainz
Maëlle Bochud: University of Fribourg
Valérie Brügger-Verdon: University of Fribourg
Maren Gerhards: Johannes Gutenberg University Mainz
Felicia Schön: Johannes Gutenberg University Mainz
Franka Dorndecker: Johannes Gutenberg University Mainz
Dies Meijer: University of Edinburgh
Robert Fledrich: University of Leipzig
Ruth Stassart: University of Leipzig
Devanarayanan Siva Sankar: University of Fribourg
Jörn Dengjel: University of Fribourg
Sofía Raigón López: Johannes Gutenberg University Mainz
Claire Jacob: Johannes Gutenberg University Mainz

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract After a peripheral nerve injury, Schwann cells (SCs), the myelinating glia of the peripheral nervous system, convert into repair cells that foster axonal regrowth, and then remyelinate or re-ensheath regenerated axons, thereby ensuring functional recovery. The efficiency of this mechanism depends however on the time needed for axons to regrow. Here, we show that ablation of histone deacetylase 8 (HDAC8) in SCs accelerates the regrowth of sensory axons and sensory function recovery. We found that HDAC8 is specifically expressed in sensory SCs and regulates the E3 ubiquitin ligase TRAF7, which destabilizes hypoxia-inducible factor 1-alpha (HIF1α) and counteracts the phosphorylation and upregulation of c-Jun, a major inducer of the repair SC phenotype. Our study indicates that this phenotype switch is regulated by different mechanisms in sensory and motor SCs and is accelerated by HDAC8 downregulation, which promotes sensory axon regeneration and sensory function recovery.

Date: 2025
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DOI: 10.1038/s41467-025-55835-9

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