Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices

Michelle S. Huang, Bauer L. LeSavage, Sadegh Ghorbani, Aidan E. Gilchrist, Julien G. Roth, Carla Huerta-López, Esther A. Mozipo, Renato S. Navarro and Sarah C. Heilshorn ()
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Michelle S. Huang: Stanford University
Bauer L. LeSavage: Stanford University
Sadegh Ghorbani: Stanford University
Aidan E. Gilchrist: University of California, Davis
Julien G. Roth: Stanford University School of Medicine
Carla Huerta-López: Stanford University
Esther A. Mozipo: Stanford University
Renato S. Navarro: Stanford University
Sarah C. Heilshorn: Stanford University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Neural progenitor cells (NPCs) hold immense potential as therapeutic candidates for neural regeneration, and materials-based strategies have emerged as attractive options for NPC expansion. However, maintaining NPC stemness has proven challenging in vitro, due to their propensity to form cell-dense neurospheres. While neurospheres promote cell–cell interactions required for NPC stem maintenance, they also restrict oxygen transport, leading to hypoxia and limited cell expansion. To overcome these limitations, we investigate two materials-based approaches to maintain NPC stemness: 1) physical matrix remodeling within a viscoelastic, stress-relaxing hydrogel and 2) matrix-induced N-cadherin-like signaling through a cell-instructive peptide. While viscoelasticity alone is sufficient to maintain NPC stemness compared to an elastic environment, NPCs still preferentially form neurospheres. The addition of N-cadherin-like peptides promotes a distributed culture of NPCs while maintaining their stemness through cadherin-mediated signaling, ultimately exhibiting improved long-term expansion and neural differentiation. Thus, our findings reveal matrix viscoelasticity and engineered N-cadherin-like interactions as having a synergistic effect on NPC expansion and differentiation within 3D matrices.

Date: 2025
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DOI: 10.1038/s41467-025-60540-8

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