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Extensive restoration of forelimb function in primates with spinal cord injury by neural stem cell transplantation

Nature Biotechnology (2025)Cite this article

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Abstract

Research on cell therapy for spinal cord injury has yet to achieve sufficient functional recovery. Previous studies in the field grafted oligodendrocyte progenitors, nonspinal neural stem cells or primary spinal neural progenitors. Here we sought to improve functional outcomes by grafting clinically compatible spinal cord neural stem cells derived from human embryonic stem cells (H9-scNSCs). H9-scNSCs significantly improved functional outcomes on a skilled hand task 9.2-fold (P = 2.5 × 10−27) in hemisected subjects compared with lesioned controls, achieving a fine object retrieval success of 53.4 ± 19.2%, and 2.9-fold (P = 6.3 × 10−8) superior to controls in hemicontused subjects. Recovery correlated with rehabilitation effort. Grafts extended up to hundreds of thousands of new axons into host circuits up to 39 mm below the injury, forming synapses with host circuitry. Lesion fill was substantially higher and differentiated cell-fate distributions were much closer to that of the normal spinal cord than in previous studies using primary spinal cord cells, likely enabling the observed superior functional outcomes.

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Fig. 1: H9-scNSC grafting in C7 hemisection lesion model supports substantial functional recovery of precision grip.
Fig. 2: Hemisection lesion extent and H9-scNSC graft filling.
Fig. 3: H9-scNSC grafts survived and extended axons into host spinal cord; host axons regenerated into grafts.
Fig. 4: H9-scNSC grafting in C6 hemicontusion lesion model.
Fig. 5: MRI scans accurately indicate graft survival.
Fig. 6: H9-scNSC grafts survive, integrate and extend axons for long distances in hemicontusion model.

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Data availability

The anatomical and behavioral data from this project are maintained in a secure, cloud-based repository platform designed to share research data, the Open Data Commons for Spinal Cord Injury (https://odc-sci.org/), ODC-SCI:1485 (https://doi.org/10.34945/F5V59G).

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Acknowledgements

This work was supported by the Veterans Administration (Gordon Mansfield SCI Collaborative Consortium, RR&D B7332R, to M.H.T.), NIH (R01 NS104442, to M.H.T.; R01 NS105478, to J.C.B. and M.S.B.; R01 NS042291, to E.S.R.), Natural Sciences and Engineering Research Council of Canada (RGPIN 2018-06382, to C.J.S.), Canada Foundation for Innovation, the Craig H. Neilsen Foundation (to M.H.T., J.C.B. and M.S.B.), the Bernard and Anne Spitzer Charitable Trust (to M.H.T.) and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.H.T.). Development of the contusion model was also supported by grants from the Neilsen Foundation and the NIH (R01 NS105478, to M.S.B. and J.C.B.). The consortium data and statistical coordinating center was supported by RR&D I01RX002245 (to A.R.F.). We thank E. Mendoza for statistical programming support.

Author information

Author notes

  1. These authors contributed equally: Eleni Sinopoulou, Ephron S. Rosenzweig.

Authors and Affiliations

  1. Dept. of Neurosciences, University of California, San Diego, La Jolla, CA, USA

    Eleni Sinopoulou, Ephron S. Rosenzweig, John H. Brock, Hiromi Kumamaru, Michael J. Castle, Janet L. Weber, Michelle W. Chow & Mark H. Tuszynski

  2. Veterans Administration Medical Center, La Jolla, CA, USA

    John H. Brock & Mark H. Tuszynski

  3. Dept. of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA

    Ernesto A. Salegio, J. Russell Huie, Nikos Kyritsis, Adam R. Ferguson, Michael S. Beattie & Jacqueline C. Bresnahan

  4. California National Primate Research Center, University of California, Davis, Davis, CA, USA

    Rachele Wurr & Ryan Macon

  5. Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Leif A. Havton

  6. Veterans Administration Medical Center, Bronx, NY, USA

    Leif A. Havton

  7. College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

    Yvette S. Nout-Lomas

  8. Mechatronic Systems Engineering, Simon Fraser University, Surrey, British Columbia, Canada

    Carolyn J. Sparrey

  9. International Collaboration on Repair Discoveries (ICORD), Vancouver, British Columbia, Canada

    Carolyn J. Sparrey

  10. Veterans Administration Medical Center, San Francisco, CA, USA

    Adam R. Ferguson

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Contributions

E.S., E.S.R., J.H.B., H.K., E.A.S., M.J.C., J.L.W., R.W., R.M., M.W.C., J.R.H., N.K., L.A.H., Y.S.N.-L., C.J.S., A.R.F., M.S.B., J.C.B. and M.H.T. designed the experiments. E.S., E.S.R., E.A.S., Y.S.N.-L., C.J.S., M.S.B., J.C.B. and M.H.T. performed surgery. E.S., E.S.R., J.H.B., J.L.W., R.W., R.M. and M.W.C. processed tissue. E.S., E.S.R., J.H.B., E.A.S., J.L.W., M.W.C., J.R.H. and N.K. imaged tissue. E.S., E.S.R., J.H.B., H.K., E.A.S., M.J.C., J.R.H., N.K., C.J.S., A.R.F., M.S.B., J.C.B. and M.H.T. analyzed the data. E.S., E.S.R., J.H.B., J.R.H., N.K., L.A.H., Y.S.N.-L., C.J.S., A.R.F., M.S.B., J.C.B. and M.H.T. wrote the paper. E.S., E.S.R., J.H.B., J.R.H., N.K., L.A.H., Y.S.N.-L., C.J.S., A.R.F., M.S.B., J.C.B. and M.H.T. edited the paper.

Corresponding author

Correspondence to Mark H. Tuszynski.

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Extended data

Extended Data Fig. 1 Graft Vascularization.

Labeling for von Willebrand factor (vWF) shows extensive vascularization of grafts, shown at various magnifications. See Methods regarding sampling methods and reproducibility. Scale Bars: A, 1 mm; B, 200 µm; C, 50 µm.

Extended Data Fig. 2 H9-scNSC Grafts in Monkeys that Underwent Hemi-contusions.

(A) S121 labeling for human cells demonstrates grafts in lesion sites of each contused monkey. There is excellent graft fill of the lesion site in 6 monkeys (#’s 9, 11-15). One monkey, #10, has surviving graft in only the rostral portion of the lesion site: this monkey therefore had very few detectable caudal axons (Fig. 6g). Monkey #10 also exhibited good functional improvement, but had the smallest contusion lesion volume among all animals (less than half the size of the mean lesion volume) and considerable right-sided tissue sparing. Thus, recovery in this subject was likely attributable to lesion incompleteness. (B) S121 labeling in contused monkeys lacking surviving grafts. Scale Bars: 1 mm.

Extended Data Fig. 3 NeuN Expression in Graft.

(A) Low-magnification view encompassing ~9 mm2 of neural stem cell graft. S121 label for human cells, NeuN label for neurons. (B) Same field of view, NeuN. Some clustering of neurons is evident. Scale Bar: 500 µm.

Extended Data Fig. 4 Olig2 Expression in Graft.

(A) Olig2-expressing cells (oligodendrocyte progenitors and both immature and mature oligodendrocytes) were distributed throughout grafts, comprising 9 ± 2% of total grafted cells. NeuN labeling shown in blue. (B) Confocal image of four Olig2+ cells (arrows) in the graft. DAPI labeling shown in gray. See Methods regarding sampling methods and reproducibility. Scale Bars: A, 100 µm; B, 10 µm.

Extended Data Table 1 Hemisected Subject Data
Full size table
Extended Data Table 2 Contused Subject Data
Full size table

Supplementary information

Reporting Summary

Supplementary Video 1

Right Hand Use in Grafted Hemisected Subject. Grafted hemisection subject (Monkey #2) can use right hand digits 1-3 (D1-3) in pincer motion to remove and eat a tomato from a small cup.

Supplementary Video 2

Right Hand Use in Hemisected Control Subject. Ungrafted hemisection control subject (Monkey #5) 15 weeks post injury. During manipulation and eating of a piece of fruit in the exercise cage, right hand remains in closed fist during food manipulation: digit 1(D1) is tucked in under digits 2 (D2) and 3 (D3). Left hand is normal.

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Sinopoulou, E., Rosenzweig, E.S., Brock, J.H. et al. Extensive restoration of forelimb function in primates with spinal cord injury by neural stem cell transplantation. Nat Biotechnol (2025). https://doi.org/10.1038/s41587-025-02865-9

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