ORCID ID

C. Kothapalli https://orcid.org/0000-0001-8450-0640

Document Type

Article

Publication Date

4-2026

Publication Title

Journal of Materials Chemistry B

Abstract

Spinal cord injury (SCI) leads to a complex remodeling of the extracellular matrix (ECM), where Tenascin-C (TNC) is strongly upregulated during the early phases of the injury cascade. While TNC is known to influence neural cell behavior, its functional role and mode of presentation in guiding neuronal differentiation remains unclear. In this study, we developed a stiffness-controlled methacrylated hyaluronic acid (MeHA) hydrogel platform that mimics the mechanical properties of the spinal cord and enables defined matrix immobilization of TNC. In vivo analyses showed elevated TNC expression from day 1, with the strongest perilesional signal during the subacute period (1 week-1 month). Using this temporal insight, we investigated the role of matrix-bound versus soluble TNC in directing neuronal differentiation of induced spinal cord progenitor cells in vitro. Immobilized TNC presented with naïve spinal cord stiffness matched MeHA substrates significantly enhanced neuronal and motor neuron differentiation, as evidenced by increased beta III-tubulin and ISL1 expression, compared to soluble TNC or unmodified controls. These effects were strongly dependent on both ligand concentration and matrix stiffness, highlighting a narrow bioactive window for TNC-mediated signaling (effective window: 100-200 nM; reduced responses at >= 300 nM). Furthermore, bulk 3D MeHA hydrogels functionalized with TNC supported cell viability and sustained neuronal differentiation, demonstrating translational relevance for future scaffold-based neural repair. These findings identify TNC as a matrix-bound bioactive cue that interacts with the mechanical environment to regulate neuronal lineage commitment, providing a framework for designing next-generation biomaterials for neural repair.

Comments

The authors would like to acknowledge partial funding from the National Science Foundation (NSF) Division of Chemical, Bioengineering, Environmental and Transport Systems (CBET) award numbers CBET-2042117 (University of Akron, PI N.D. Leipzig) and CBET-2042116 (Cleveland State University, PI C.R. Kothapalli) as well as partial funding from the Congressionally Directed Medical Research Programs (CDMRP) via the Spinal Cord Injury Research Program (SCIRP) award number SC220128.

DOI

10.1039/d6tb00247a

Version

Publisher's PDF

Creative Commons License

Creative Commons Attribution-Noncommercial 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 License

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