Functional synaptic connectivity of engrafted spinal cord neurons with hindlimb motor circuitry in the injured spinal cord
Spinal cord injury (SCI) results in significant neurological deficits, and curative therapies are lacking. Neural progenitor cell (NPC) transplantation shows promise, as graft-derived neurons (GDNs) can integrate into host spinal cord and support axon regeneration. Here, we examined the synaptic integration of GDNs into hindlimb motor circuits in a mouse thoracic contusion SCI model. Transsynaptic tracing revealed that GDNs form synaptic connections with host motor circuits. Axon mapping showed distinct termination patterns of cholinergic and V2a interneurons within host spinal cord. Chemogenetic activation of GDNs induced muscle activity in a subset of transplanted animals, but NPC transplantation alone did not improve locomotor recovery. These findings indicate that GDNs can integrate into and modulate activity of host circuits, yet limited synaptic connectivity constrains functional recovery. Future studies should enhance graft-host connectivity and refine transplantation strategies to maximize therapeutic benefit for SCI.
Authors
- Frank L. Jalufka (ORCID: https://orcid.org/0000-0003-3704-443X)
- Arshi Tandon
- Ashley Smith (ORCID: https://orcid.org/0000-0001-7156-5533)
- Ashley Tucker (ORCID: https://orcid.org/0000-0001-8661-5417)
- Victoria E. Abraira (ORCID: https://orcid.org/0000-0001-9936-9921)
- Michael S. Totty (ORCID: https://orcid.org/0000-0002-9292-8556)
- Hannah Thomas
- Jennifer N. Dulin (ORCID: https://orcid.org/0000-0001-5767-4290)
- Miriam Aceves (ORCID: https://orcid.org/0000-0002-1778-0213)
- Joshua K. Thackray (ORCID: https://orcid.org/0000-0003-2828-452X)
- K.N.C. Vo (ORCID: https://orcid.org/0009-0000-8855-0549)
- Stephen Maren (ORCID: https://orcid.org/0000-0002-9342-7411)
- Andrew F. Adler (ORCID: https://orcid.org/0000-0001-8053-3971)
- Heath Blackmon (ORCID: https://orcid.org/0000-0002-5433-4036)
- Sunjay Letchuman (ORCID: https://orcid.org/0000-0001-5535-7910)
- Michael Pitonak (ORCID: https://orcid.org/0000-0003-2638-0323)
- Jaclyn T. Eisdorfer (ORCID: https://orcid.org/0000-0003-3285-3473)
- Dylan A. McCreedy (ORCID: https://orcid.org/0000-0003-2413-0793)
- Sneha Nadella
- Angelina Baltazar
- Julius Jang
- Tucker Gillespie
- Joshua Moses
- Anna Pauken
- Brendan Singletary (ORCID: https://orcid.org/0009-0007-6154-0544)
Institutions
- Rutgers, The State University of New Jersey (US)
- University of Illinois Urbana-Champaign (US)
- Novo Nordisk (Denmark) (DK)
- Texas A&M University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1038/s41467-025-65395-7
- Citations
- 1
- Primary Topic
- Nerve injury and regeneration
- Type
- article
- Field-Weighted Citation Impact
- 0.91
Funders
- Paralyzed Veterans of America Research Foundation
- Paralyzed Veterans of America
- Wings for Life
- National Institutes of Health
- National Institute on Drug Abuse