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Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

Tao, Yunlong ; Vermilyea, Scott C ; Zammit, Matthew ; Lu, Jianfeng ; Olsen, Miles ; Metzger, Jeanette M ; Yao, Lin ; Chen, Yuejun ; Phillips, Sean ; Holden, James E ; Bondarenko, Viktoriya ; Block, Walter F ; Barnhart, Todd E ; Schultz-Darken, Nancy ; Brunner, Kevin ; Simmons, Heather ; Christian, Bradley T ; Emborg, Marina E ; Zhang, Su-Chun

Nature medicine, 2021-04, Vol.27 (4), p.632-639 [Periódico revisado por pares]

United States: Nature Publishing Group

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Título:
Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
Autor: Tao, Yunlong ; Vermilyea, Scott C ; Zammit, Matthew ; Lu, Jianfeng ; Olsen, Miles ; Metzger, Jeanette M ; Yao, Lin ; Chen, Yuejun ; Phillips, Sean ; Holden, James E ; Bondarenko, Viktoriya ; Block, Walter F ; Barnhart, Todd E ; Schultz-Darken, Nancy ; Brunner, Kevin ; Simmons, Heather ; Christian, Bradley T ; Emborg, Marina E ; Zhang, Su-Chun
Assuntos: Autografts ; Basal ganglia ; Behavior ; Central nervous system diseases ; Clinical trials ; Degeneration ; Dihydroxyphenylalanine ; Dopamine ; Dopamine receptors ; Fetuses ; Immunosuppression ; Levodopa ; Mathematical models ; Mesencephalon ; Model testing ; Monkeys ; Monkeys & apes ; Movement disorders ; Neural stem cells ; Neurodegeneration ; Neurodegenerative diseases ; Neurons ; Parkinson's disease ; Pathogenesis ; PD-1 protein ; Pluripotency ; Positron emission ; Positron emission tomography ; Primates ; Recovery ; Robustness (mathematics) ; Signs and symptoms ; Stem cell transplantation ; Stem cells ; Tissues ; Tomography ; Transplantation ; Transplants & implants
É parte de: Nature medicine, 2021-04, Vol.27 (4), p.632-639
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Y.T. reprogrammed the monkey iPSC, performed the cell culture, DA differentiation, immunostaining, transplantation, data analysis and interpretation, and wrote the manuscript, S.V., K.B., & J. M. performed MPTP post-surgical care and cell transplantation, M.Z. & J.H. produced the PET images and related analysis. J.L. & 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.& 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, SC.Z. conceived and designed the experiments, data analysis and interpretation and wrote the manuscript.
Author contributions
Descrição: 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 PD . Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues . 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys

United States: Nature Publishing Group

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