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; Kenneth D Poss

doi:10.1038/s41467-023-40486-5

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

Nat Commun. 2023 Aug 11;14(1):4857. doi: 10.1038/s41467-023-40486-5.

Authors

Valentina Cigliola^{1

2

3}, Adam Shoffner^{1

2

4}, Nutishia Lee^{1

2}, Jianhong Ou^{1

2}, Trevor J Gonzalez⁵, Jiaul Hoque⁶, Clayton J Becker^{1

2}, Yanchao Han⁷, Grace Shen^{1

2}, Timothy D Faw^{1

6

8}, Muhammad M Abd-El-Barr⁹, Shyni Varghese^{6

10

11}, Aravind Asokan^{1

4

5

11}, Kenneth D Poss^{12

13}

Affiliations

¹ Duke Regeneration Center, Duke University, Durham, NC, USA.
² Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
³ Université Côte d'Azur, Inserm, CNRS, Institut de Biologie Valrose, Nice, France.
⁴ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
⁵ Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, USA.
⁶ Department of Orthopedic Surgery, Duke University School of Medicine, Durham, NC, USA.
⁷ Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Soochow University, Suzhou, Jiangsu, China.
⁸ Duke Institute for Brain Sciences, Duke University, Durham, NC, USA.
⁹ Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.
¹⁰ Department of Mechanical Engineering and Materials Science, Duke University, Durham, NC, USA.
¹¹ Department of Biomedical Engineering, Duke University, Durham, NC, USA.
¹² Duke Regeneration Center, Duke University, Durham, NC, USA. [email protected].
¹³ Department of Cell Biology, Duke University Medical Center, Durham, NC, USA. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Axons / metabolism
Heparin-binding EGF-like Growth Factor / genetics
Heparin-binding EGF-like Growth Factor / metabolism
Humans
Mammals
Mice
Nerve Regeneration / genetics
Spinal Cord / metabolism
Spinal Cord Injuries* / genetics
Spinal Cord Injuries* / metabolism
Spinal Cord Injuries* / therapy
Spinal Cord Regeneration* / physiology
Zebrafish / genetics

Substances

Heparin-binding EGF-like Growth Factor
HBEGF protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding