An injectable COL6-crosslinked HA-DTPH hydrogel promotes spinal tract-like structure organization during spinal cord regeneration

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Vol. 495; p. 153296
• Main Authors: Sun, Jia-Hui, Fang, Zhou, Li, Zhiling, Zheng, Ting-Ting, Liu, Sheng, Zhu, Jixiang, Lin, Wensheng, Zhang, Li-Kang, Yin, Aihua, Xuan, Aiguo, Zou, Jian-Long
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.09.2024
• Subjects: Morphogenesis; Nerve bundle; Nerve regeneration; Self-organization; Spinal cord injury; Tissue engineering; Morphogenesis; Spinal cord injury; Tissue engineering; Nerve regeneration; Self-organization; Nerve bundle
• ISSN: 1385-8947
• DOI: 10.1016/j.cej.2024.153296

[Display omitted] An HAPC hydrogel composed of hyaluronic acid, laminin peptide, and COL6 was utilized to fill the cavity of a spinal cord transection injury. This treatment inhibits glial scar formation, promotes axonal regeneration, and more importantly, reactivates endogenous nerve tract morphogenesis through the COL6-NCAM1 pathway, leading to structured spinal cord regeneration along with better functional recovery. •The adult and regenerative spinal cord lacks COL6-NCAM1 pathway.•A COL6-crosslinked hydrogel (HAPC) reactivates spinal tract morphogenesis during regeneration.•Straight nerve tract formation is driven by axonal aggregation and proximal retraction.•Reconstruction of spinal tracts facilitates animal functional recovery. Serious spinal cord injury (SCI) often leads to disorganized axon regeneration, impeding the accurate projection of neural signals. This study aims to rebuild spinal tracts by targeting the collagen VI (COL6)-induced axonal fasciculation pathway, which is active during spinal cord development but diminishes in regenerating spinal cord. A thiol-modified hyaluronic acid hydrogel crosslinked with COL6 (HAPC) is proposed to reactivate spinal tract morphogenesis for regeneration. Neurites cultured on the HAPC substrate exhibited a straight-bundled pattern, contrasting with the straggly pattern observed in control groups that lacked COL6. The dynamics of axonal aggregation and proximal retraction are determined to drive the formation of straight axon bundles. Experiments on a rat spinal cord transection model demonstrates that treatment with HAPC significantly induces the organization of spinal tract-like structures and promotes the targeted projection of 5-Hydroxytryptamine (5-HT) axons, along with improved functional recovery. These findings highlight the role of COL6 in spinal tract self-organization and the potential of HAPC for treating clinical SCI.