Spinal injury induces a stem cell-like progenitor state that promotes regenerative neurogenesis via clcf1 in zebrafish.

Westphal, M.; Branch, R.; Docampo-Seara, A.; Cosacak, M. I.; Logvinova, E.; Bellia, M.; Cheng, S.; Tsarouchas, T. M.; Bretschneider, A.; Zoeller, D.; Shen, R.; Scucces, L.; Baerhold, D.; Becker, T.; Becker, C. G.

doi:10.64898/2026.06.25.734505

bioRxiv · 10.64898/2026.06.25.734505

Spinal injury induces a stem cell-like progenitor state that promotes regenerative neurogenesis via clcf1 in zebrafish.

Westphal, M.·Branch, R.·Docampo-Seara, A.·Cosacak, M. I.·Logvinova, E.·Bellia, M.·Cheng, S.·Tsarouchas, T. M.·Bretschneider, A.·Zoeller, D.·Shen, R.·Scucces, L.·Baerhold, D.·Becker, T.·Becker, C. G.

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Abstract

After spinal injury, zebrafish, in contrast to mammals, show regenerative neurogenesis, characterized by enhanced injury-induced proliferation of ependymo-radial glial cells (ERGs) and an increase in injury-induced generation of neurons from these progenitors. It is unclear whether regenerative neurogenesis simply recapitulates development or uses regeneration-specific mechanisms. Using scRNA-seq and in vivo validation we find a spinal injury-induced state in ERGs (iiERGs) in larval zebrafish. This cell state emerges mostly without proliferation and has stem cell characteristics, including weak expression of neurogenic genes and strong expression of stemness factors, such as lin28a. Expression of lin28a is not detectable during ongoing developmental neurogenesis. Following spinal cord lesion, lin28a disruption increases the numbers of ERGs undergoing neuronal differentiation and of newly-generated neurons, at the expense of proliferating ERGs and iiERGs. This supports a stemness-preserving role of lin28a in iiERGs. Importantly, iiERGs secrete growth factors, including the regeneration-specific cytokine clcf1, which depends in part on lin28a expression. Disruption of clcf1 signalling impairs spinal progenitor proliferation and injury-induced generation of new neurons, but does not affect the emergence of iiERGs. Over-expression of clcf1 is sufficient to augment neurogenesis in unlesioned animals without inducing the iiERG state, indicating that clcf1 acts as a generic growth factor. Hence, we describe an injury-specific stem cell-like ERG population that regulates regenerative neurogenesis by attenuating neuronal differentiation via lin28a and promoting progenitor proliferation via clcf1.

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Westphal, M., Branch, R., Docampo-Seara, A., Cosacak, M. I., Logvinova, E., Bellia, M., Cheng, S., Tsarouchas, T. M., Bretschneider, A., Zoeller, D., Shen, R., Scucces, L., Baerhold, D., Becker, T., Becker, C. G.. 2026-06-30. Spinal injury induces a stem cell-like progenitor state that promotes regenerative neurogenesis via clcf1 in zebrafish.. https://doi.org/10.64898/2026.06.25.734505

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