Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer

Valentina Cigliola, Adam Shoffner, Nutishia Lee, Jianhong Ou, Trevor J. Gonzalez, Jiaul Hoque, Clayton J. Becker, Yanchao Han, Grace Shen, Timothy D. Faw, Muhammad M. Abd-El-Barr, Shyni Varghese, Aravind Asokan and Kenneth D. Poss ()
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Valentina Cigliola: Duke University
Adam Shoffner: Duke University
Nutishia Lee: Duke University
Jianhong Ou: Duke University
Trevor J. Gonzalez: Duke University School of Medicine
Jiaul Hoque: Duke University School of Medicine
Clayton J. Becker: Duke University
Yanchao Han: Soochow University
Grace Shen: Duke University
Timothy D. Faw: Duke University
Muhammad M. Abd-El-Barr: Duke University Medical Center
Shyni Varghese: Duke University School of Medicine
Aravind Asokan: Duke University
Kenneth D. Poss: Duke University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Unlike adult mammals, zebrafish regenerate spinal cord tissue and recover locomotor ability after a paralyzing injury. Here, we find that ependymal cells in zebrafish spinal cords produce the neurogenic factor Hb-egfa upon transection injury. Animals with hb-egfa mutations display defective swim capacity, axon crossing, and tissue bridging after spinal cord transection, associated with disrupted indicators of neuron production. Local recombinant human HB-EGF delivery alters ependymal cell cycling and tissue bridging, enhancing functional regeneration. Epigenetic profiling reveals a tissue regeneration enhancer element (TREE) linked to hb-egfa that directs gene expression in spinal cord injuries. Systemically delivered recombinant AAVs containing this zebrafish TREE target gene expression to crush injuries of neonatal, but not adult, murine spinal cords. Moreover, enhancer-based HB-EGF delivery by AAV administration improves axon densities after crush injury in neonatal cords. Our results identify Hb-egf as a neurogenic factor necessary for innate spinal cord regeneration and suggest strategies to improve spinal cord repair in mammals.

Date: 2023
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DOI: 10.1038/s41467-023-40486-5

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