Development of an N‑Cadherin Biofunctionalized Hydrogel to Support the Formation of Synaptically Connected Neural Networks

In vitro models of the human central nervous system (CNS), particularly those derived from induced pluripotent stem cells (iPSCs), are becoming increasingly recognized as useful complements to animal models for studying neurological diseases and developing therapeutic strategies. However, many curre...

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Bibliographic Details
Published in:	ACS biomaterials science & engineering Vol. 6; no. 10; pp. 5811 - 5822
Main Authors:	O’Grady, Brian J, Balotin, Kylie M, Bosworth, Allison M, McClatchey, P. Mason, Weinstein, Robert M, Gupta, Mukesh, Poole, Kara S, Bellan, Leon M, Lippmann, Ethan S
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 12-10-2020
Subjects:	Animals Cadherins Gelatin Humans Hydrogels Induced Pluripotent Stem Cells Neural Networks, Computer Tissue Engineering and Regenerative Medicine neuron induced pluripotent stem cell biomaterial hydrogel neural network
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Summary:	In vitro models of the human central nervous system (CNS), particularly those derived from induced pluripotent stem cells (iPSCs), are becoming increasingly recognized as useful complements to animal models for studying neurological diseases and developing therapeutic strategies. However, many current three-dimensional (3D) CNS models suffer from deficits that limit their research utility. In this work, we focused on improving the interactions between the extracellular matrix (ECM) and iPSC-derived neurons to support model development. The most common ECMs used to fabricate 3D CNS models often lack the necessary bioinstructive cues to drive iPSC-derived neurons to a mature and synaptically connected state. These ECMs are also typically difficult to pattern into complex structures due to their mechanical properties. To address these issues, we functionalized gelatin methacrylate (GelMA) with an N-cadherin (Cad) extracellular peptide epitope to create a biomaterial termed GelMA-Cad. After photopolymerization, GelMA-Cad forms soft hydrogels (on the order of 2 kPa) that can maintain patterned architectures. The N-cadherin functionality promotes survival and maturation of single-cell suspensions of iPSC-derived glutamatergic neurons into synaptically connected networks as determined by viral tracing and electrophysiology. Immunostaining reveals a pronounced increase in presynaptic and postsynaptic marker expression in GelMA-Cad relative to Matrigel, as well as extensive colocalization of these markers, thus highlighting the biological activity of the N-cadherin peptide. Overall, given its ability to enhance iPSC-derived neuron maturity and connectivity, GelMA-Cad should be broadly useful for in vitro studies of neural circuitry in health and disease.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Co-senior author Co-first author
ISSN:	2373-9878 2373-9878
DOI:	10.1021/acsbiomaterials.0c00885