Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices
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 ce...
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| Format: | Article |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60540-8 |
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| author | Michelle S. Huang Bauer L. LeSavage Sadegh Ghorbani Aidan E. Gilchrist Julien G. Roth Carla Huerta-López Esther A. Mozipo Renato S. Navarro Sarah C. Heilshorn |
| author_facet | Michelle S. Huang Bauer L. LeSavage Sadegh Ghorbani Aidan E. Gilchrist Julien G. Roth Carla Huerta-López Esther A. Mozipo Renato S. Navarro Sarah C. Heilshorn |
| author_sort | Michelle S. Huang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-061736bd680f41d88e60ebcd050fb1b7 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-061736bd680f41d88e60ebcd050fb1b72025-08-20T03:10:34ZengNature PortfolioNature Communications2041-17232025-06-0116111710.1038/s41467-025-60540-8Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matricesMichelle S. Huang0Bauer L. LeSavage1Sadegh Ghorbani2Aidan E. Gilchrist3Julien G. Roth4Carla Huerta-López5Esther A. Mozipo6Renato S. Navarro7Sarah C. Heilshorn8Department of Chemical Engineering, Stanford UniversityDepartment of Bioengineering, Stanford UniversityDepartment of Materials Science and Engineering, Stanford UniversityDepartment of Biomedical Engineering, University of California, DavisInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineDepartment of Materials Science and Engineering, Stanford UniversityDepartment of Bioengineering, Stanford UniversityDepartment of Materials Science and Engineering, Stanford UniversityDepartment of Materials Science and Engineering, Stanford UniversityAbstract 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.https://doi.org/10.1038/s41467-025-60540-8 |
| spellingShingle | Michelle S. Huang Bauer L. LeSavage Sadegh Ghorbani Aidan E. Gilchrist Julien G. Roth Carla Huerta-López Esther A. Mozipo Renato S. Navarro Sarah C. Heilshorn Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices Nature Communications |
| title | Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices |
| title_full | Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices |
| title_fullStr | Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices |
| title_full_unstemmed | Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices |
| title_short | Viscoelastic N‑cadherin-like interactions maintain neural progenitor cell stemness within 3D matrices |
| title_sort | viscoelastic n cadherin like interactions maintain neural progenitor cell stemness within 3d matrices |
| url | https://doi.org/10.1038/s41467-025-60540-8 |
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