Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

Abstract

Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson’s disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD1. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues1,2. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Behavior evaluation of transplanted monkeys.
Fig. 2: Graft evaluation in vivo by PET.
Fig. 3: Histological analysis of grafts.
Fig. 4: Correlation analysis between behavior recovery, PET and DA neurons in grafts.

Data availability

All requests for raw and analyzed data and materials will be promptly reviewed by the corresponding author and the University of Wisconsin–Madison to verify whether the request is subject to any intellectual property or confidentiality obligations. Any data and materials that can be shared will be released via a material transfer agreement.

References

  1. 1.

    Bjorklund, A. & Lindvall, O. Replacing dopamine neurons in Parkinson’s disease: how did it happen? J. Parkinsons Dis. 7, S21–S31 (2017).

    Article  Google Scholar 

  2. 2.

    Barker, R. A., Barrett, J., Mason, S. L. & Bjorklund, A. Fetal dopaminergic transplantation trials and the future of neural grafting in Parkinson’s disease. Lancet Neurol. 12, 84–91 (2013).

    CAS  Article  Google Scholar 

  3. 3.

    Kriks, S. et al. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 480, 547–551 (2011).

    CAS  Article  Google Scholar 

  4. 4.

    Kikuchi, T. et al. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model. Nature 548, 592–596 (2017).

    CAS  Article  Google Scholar 

  5. 5.

    Barker, R. A., Parmar, M., Studer, L. & Takahashi, J. Human trials of stem cell-derived dopamine neurons for Parkinson’s disease: dawn of a new era. Cell Stem Cell 21, 569–573 (2017).

    CAS  Article  Google Scholar 

  6. 6.

    Emborg, M. E. et al. Induced pluripotent stem cell-derived neural cells survive and mature in the nonhuman primate brain. Cell Rep. 3, 646–650 (2013).

    CAS  Article  Google Scholar 

  7. 7.

    Hallett, P. J. et al. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell 16, 269–274 (2015).

    CAS  Article  Google Scholar 

  8. 8.

    Schweitzer, J. S. et al. Personalized iPSC-Derived dopamine progenitor cells for Parkinson’s disease. N. Engl. J. Med. 382, 1926–1932 (2020).

    CAS  Article  Google Scholar 

  9. 9.

    Fusaki, N., Ban, H., Nishiyama, A., Saeki, K. & Hasegawa, M. Efficient induction of transgene-free human pluripotent stem cells using a vector based on Sendai virus, an RNA virus that does not integrate into the host genome. Proc. Jpn Acad. Ser. B Phys. Biol. Sci. 85, 348–362 (2009).

    CAS  Article  Google Scholar 

  10. 10.

    Xi, J. et al. Specification of midbrain dopamine neurons from primate pluripotent stem cells. Stem Cells 30, 1655–1663 (2012).

    CAS  Article  Google Scholar 

  11. 11.

    Reeve, A., Simcox, E. & Turnbull, D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 14, 19–30 (2014).

    CAS  Article  Google Scholar 

  12. 12.

    Freed, C. R. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N. Engl. J. Med. 344, 710–719 (2001).

    CAS  Article  Google Scholar 

  13. 13.

    Takagi, Y. et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J. Clin. Invest. 115, 102–109 (2005).

    CAS  Article  Google Scholar 

  14. 14.

    Daadi, M. M., Grueter, B. A., Malenka, R. C., Redmond, D. E. Jr. & Steinberg, G. K. Dopaminergic neurons from midbrain-specified human embryonic stem cell-derived neural stem cells engrafted in a monkey model of Parkinson’s disease. PLoS ONE 7, e41120 (2012).

    CAS  Article  Google Scholar 

  15. 15.

    Wakeman, D. R. et al. Survival and integration of neurons derived from human embryonic stem cells in MPTP-lesioned primates. Cell Transplant. 23, 981–994 (2014).

    Article  Google Scholar 

  16. 16.

    Gonzalez, C., Bonilla, S., Flores, A. I., Cano, E. & Liste, I. An update on human stem cell-based therapy in Parkinson’s disease. Curr. Stem Cell Res. Ther. 11, 561–568 (2016).

    CAS  Article  Google Scholar 

  17. 17.

    Kikuchi, T. et al. Survival of human induced pluripotent stem cell-derived midbrain dopaminergic neurons in the brain of a primate model of Parkinson’s disease. J. Parkinsons Dis. 1, 395–412 (2011).

    CAS  Article  Google Scholar 

  18. 18.

    Wang, Y. K. et al. Human clinical-grade parthenogenetic ESC-derived dopaminergic neurons recover locomotive defects of nonhuman primate models of Parkinson’s disease. Stem Cell Rep. 11, 171–182 (2018).

    CAS  Article  Google Scholar 

  19. 19.

    Wang, S. et al. Autologous iPSC-derived dopamine neuron transplantation in a nonhuman primate Parkinson’s disease model. Cell Disco. 1, 15012 (2015).

    Article  Google Scholar 

  20. 20.

    Emborg-Knott, M. E. & Domino, E. F. MPTP-Induced hemiparkinsonism in nonhuman primates 6-8 years after a single unilateral intracarotid dose. Exp. Neurol. 152, 214–220 (1998).

    CAS  Article  Google Scholar 

  21. 21.

    Gash, D. M. et al. An automated movement assessment panel for upper limb motor functions in rhesus monkeys and humans. J. Neurosci. Methods 89, 111–117 (1999).

    CAS  Article  Google Scholar 

  22. 22.

    Vermilyea, S. C. et al. Real-time intraoperative MRI intracerebral delivery of induced pluripotent stem cell-derived neurons. Cell Transplant. 26, 613–624 (2017).

    Article  Google Scholar 

  23. 23.

    Zhu, L., Ploessl, K. & Kung, H. F. PET/SPECT imaging agents for neurodegenerative diseases. Chem. Soc. Rev. 43, 6683–6691 (2014).

    CAS  Article  Google Scholar 

  24. 24.

    Ahlskog, J. E., Maraganore, D. M., Uitti, R. J. & Uhl, G. R. Brain imaging to assess the effects of dopamine agonists on progression of Parkinson disease. JAMA 288, 311 (2002).

    PubMed  Google Scholar 

  25. 25.

    Hsiao, I. T. et al. Correlation of Parkinson disease severity and 18F-DTBZ positron emission tomography. JAMA Neurol. 71, 758–766 (2014).

    Article  Google Scholar 

  26. 26.

    Tiklova, K. et al. Single cell transcriptomics identifies stem cell-derived graft composition in a model of Parkinson’s disease. Nat. Commun. 11, 2434 (2020).

    CAS  Article  Google Scholar 

  27. 27.

    Morizane, A. et al. MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat. Commun. 8, 385 (2017).

    Article  Google Scholar 

  28. 28.

    Mendez, I. et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 128, 1498–1510 (2005).

    Article  Google Scholar 

  29. 29.

    Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

    CAS  Article  Google Scholar 

  30. 30.

    Hallett, P. J. et al. Long-term health of dopaminergic neuron transplants in Parkinson’s disease patients. Cell Rep. 7, 1755–1761 (2014).

    CAS  Article  Google Scholar 

  31. 31.

    Yin, D. et al. Striatal volume differences between non-human and human primates. J. Neurosci. Methods 176, 200–205 (2009).

    Article  Google Scholar 

  32. 32.

    Kordower, J. H. et al. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies. J. Comp. Neurol. 370, 203–230 (1996).

    CAS  Article  Google Scholar 

  33. 33.

    Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113, 6544–6549 (2016).

    CAS  Article  Google Scholar 

  34. 34.

    Wu, J. et al. An alternative pluripotent state confers interspecies chimaeric competency. Nature 521, 316–321 (2015).

    CAS  Article  Google Scholar 

  35. 35.

    Jewett, D. M., Kilbourn, M. R. & Lee, L. C. A simple synthesis of [11C]dihydrotetrabenazine (DTBZ). Nucl. Med. Biol. 24, 197–199 (1997).

    CAS  Article  Google Scholar 

  36. 36.

    Innis, R. B. et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J. Cereb. Blood Flow Metab. 27, 1533–1539 (2007).

    CAS  Article  Google Scholar 

  37. 37.

    Lammertsma, A. A. & Hume, S. P. Simplified reference tissue model for PET receptor studies. Neuroimage 4, 153–158 (1996).

    CAS  Article  Google Scholar 

  38. 38.

    Ichise, M. et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. J. Cereb. Blood Flow Metab. 23, 1096–1112 (2003).

    Article  Google Scholar 

  39. 39.

    Tao, Y. et al. PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm. EMBO Rep. https://doi.org/10.15252/embr.202050000 (2020).

  40. 40.

    Ohshima-Hosoyama, S. et al. A monoclonal antibody-GDNF fusion protein is not neuroprotective and is associated with proliferative pancreatic lesions in parkinsonian monkeys. PLoS ONE 7, e39036 (2012).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the National Institutes of Health–National Institute of Neurological Disorders and Stroke (NS076352, NS096282 and NS086604), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54 HD090256), P51OD011106, the National Medical Research Council of Singapore (MOH-000212 and MOH-000207), the Dr. Ralph & Marian Falk Medical Research Trust, the University of Wisconsin–Madison Office of Vice Chancellor for Research and Graduate Education, the Cellular and Molecular Pathology Graduate Program, the Neuroscience Training Program and the Departments of Radiology and Medical Physics at the University of Wisconsin–Madison. This project was possible due to the dedication and support of Wisconsin National Primate Research Center veterinarians and animal care technicians, especially C. Boettcher, K. Fuchs and D. Schalk. We are grateful to P. Perez Toro, S. Brady, K. MacManus, A. Payne and L. Fox for facilitating behavioral testing procedures during their undergraduate studies.

Author information

Affiliations

Authors

Contributions

Y.T. reprogrammed monkey iPSCs, performed the cell culture, DA differentiation, immunostaining, transplantation, data analysis and interpretation and wrote the manuscript. S.V., K.B. and J.M. performed MPTP post-surgical care and cell transplantation. M.Z. and J.H. produced PET images and related analysis. J.L. and L.Y. reprogrammed the monkey iPSC and performed the cell culture. M.O. created the real-time intraoperative MRI targeting roadmaps and PET–MRI co-registrations. Y.C. constructed the GFP lentivirus plasmid. S.P. and N.S. collected and analyzed behavioral data and performed histological evaluations. V.B. performed immunohistochemistry. W.B. analyzed real-time intraoperative MRI targeting roadmaps. T.B. produced [11C]DTBZ. H.A.S. performed necropsies and related data interpretation. B.C. performed analysis and interpretation of PET data. M.E. conceived and designed the experiments, performed intracarotid MPTP, performed cell transplantation and animal evaluations, data analysis and interpretation and wrote the manuscript. S.-C.Z. conceived and designed the experiments, data analysis and interpretation and wrote the manuscript.

Corresponding authors

Correspondence to Marina E. Emborg or Su-Chun Zhang.

Ethics declarations

Competing interests

S.-C.Z. is a cofounder of BrainXell, Inc.

Additional information

Peer review information Jerome Staal was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Table 1 Rhesus macaques’ body weight (kg) overtime

Extended Data Fig. 1 DA neuron generation and MPTP PD model.

a, Representative images of pluripotent stem cell marker expression in iPSCs generated from rhesus macaque fibroblasts. b,c, Representative images of mDA progenitor marker (b) and DA neuron marker (c) in differentiating cells from rhesus macaque iPSCs. Scale bar: 50μm. Data are representative of at least 5 independent experiments (a-c). d, Images of TH immunostaining in the substantia nigra from allogenic and autologous rhesus monkeys. e, Stereological quantification of TH+ neurons in the substantia nigra of allogenic and autologous rhesus monkeys. f, Percentage of TH+ cell reduction in the MPTP-treated substantia nigra compared to the unlesioned side. The data are presented as mean ± s.d. (n = 5 biologically independent monkeys in each group) in e, f.

Extended Data Fig. 2 Mood behavior in transplanted monkeys.

a, The anxious pacing (AP) behavior observed in monkeys receiving allogenic or autologous transplantation from 12 months before transplantation to 24 months after transplantation. The transplantation happened at month 0. Lines show mean values for every 6 months from the allogenic group or the autologous group. b, The lack of motivation (LOM) behavior observed in monkeys receiving allogenic or autologous transplantation from 12 months before transplantation to 24 months after transplantation. c, The self-injury behavior (SIB) observed in monkeys receiving allogenic or autologous transplantation from 12 months before transplantation to 24 months after transplantation.

Extended Data Fig. 3 Graft evaluation in vivo.

a,b, Quantification of [11C]DTBZ graft binding potential in contralateral (untreated) putamen (a) and caudate (b) from allogenic and autologous monkeys before and after transplantation. The data is presented as mean ± s.d. (n = 4 per group). c,d, Quantification of the volume of uptake in contralateral (untreated) putamen (c) and contralateral caudate (d) from allogenic and autologous monkeys before and after transplantation. The data is presented as mean ± s.d. (n = 4 per group).

Extended Data Fig. 4 Overview of the graft.

a, Representative images of GFP immunostaining and Nissl staining in brain sections of allogenic and autologous animals. The red arrows point to the grafts. b, H&E staining in brain sections of allogenic and autologous animal. Enlarged images correspond to the yellow area in the respective grafts. All grafts (if present) in monkeys from both groups were examined. Data are representative of at least 3 sections having grafts from each monkey.

Extended Data Fig. 5 Histological analysis of graft.

a, Representative images of TH immunostaining in brain sections of allogenic and autologous animals. Enlarged images correspond to the grafts. b, Representative images of TH+ fiber extension area in control and MPTP brain hemisphere. c, TH immunostaining in the putamen from MPTP lesion side and unlesioned side. Scale bar: 10 µm. All grafts (if present) in monkeys from both groups were examined. Data are representative of at least 3 sections having grafts from each monkey (a-c).

Extended Data Fig. 6 Caudate graft in autologous monkeys.

Representative image of TH immunostaining in autologous monkey caudate region. The inset area is enlarged below. All grafts (if present) in monkeys from both groups were examined. Data are representative of at least 3 sections having grafts from each monkey.

Extended Data Fig. 7 Cellular composition in grafts.

a, Representative images of TH and GIRK2 or Calbindin immunostaining in grafts. Scale bars: 50 μm. b, Representative images of vGLUT1, 5-HT and GABA immunostaining in grafts. Scale bars: 50 μm. c, Representative images of COL1A1 immunostaining in and outside of grafts. scale bars: 50 μm. The white dash lines mark the edge of the graft. All grafts (if present) in monkeys from both groups were examined. Data are representative of at least 3 sections having grafts from each monkey (a-c).

Extended Data Fig. 8 Immune response evaluation in grafts.

a, Histological analysis of T cells (CD3 and CD45), microglia (CD68) and astrocyte (GFAP) marker in grafts from allogenic and autologous animals. Scale bar: 100 μm. b, Representative images of GFP and GFAP immunostaining in allogenic and autologous monkeys. Scale bar: 50 μm. The white dash lines mark the edge of the graft. All grafts (if present) in monkeys from both groups were examined. Data are representative of at least 3 sections having grafts from each monkey (a-b).

Extended Data Fig. 9 Regression analysis on the relation between DA neuron numbers and behavioral recovery/PET.

a, Linear regression analysis between ipsilateral caudate [11C]DTBZ binding potential and FMS. b, Linear regression analysis between ipsilateral caudate [11C]DTBZ binding potential and CRS. c, Linear regression analysis between ipsilateral caudate [11C]DTBZ binding potential and CRS recovery rate. d, Linear regression analysis between ipsilateral caudate [11C]DTBZ binding potential and surviving TH+ neuron numbers. e, Linear regression analysis between ipsilateral caudate [11C]DTBZ binding potential and caudate surviving TH+ neuron numbers. f, Linear regression and logistic fitting analysis of FMS and total surviving TH+ neuron numbers in grafts. The Pearson’s r, significance (p value) and R2 (coefficient of determination) were assessed by two-tailed Pearson’s correlation analysis in a-f.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tao, Y., Vermilyea, S.C., Zammit, M. et al. Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys. Nat Med 27, 632–639 (2021). https://doi.org/10.1038/s41591-021-01257-1

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing