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bioRxiv · 10.1101/2020.07.08.192591

Human embryonic stem cells-derived dopaminergic neurons transplanted in parkinsonian monkeys recover dopamine levels and motor behavior

Adolfo Lopez-Ornelas·Itzel Escobedo-Avila·Gabriel Ramirez-Garcia·Rolando Lara-Rodarte·Cesar Melendez-Ramirez·Beetsi Urrieta-Chavez·Tonatiuh Barrios-Garcia·Veronica Caceres-Chavez·Xochitl Flores-Ponce·Francia Carmona·Carlos A Reynoso·Carlos Aguilar·Nora E Kerik·Luisa Rocha·Leticia Verdugo-Diaz·Victor Trevino·Jose Bargas·Veronica Ramos-Mejia·Juan Fernandez-Ruiz·Aurelio Campos-Romo·Ivan Velasco
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Abstract

Human embryonic stem cells (hESCs) differentiate into specialized cells, including midbrain dopaminergic neurons (DAN). Non-human primates (NHPs) injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine develop some alterations observed in Parkinsons disease (PD) patients. We obtained DAN from hESCs and confirmed that they express dopaminergic markers, generate action potentials, and release dopamine (DA) in vitro. DAN were transplanted bilaterally in the putamen of parkinsonian NHPs. After grafting, animals improved motor behavior, evaluated by the HALLWAY task, and in agreement with this recovery, DA release was detected by microdialysis. Imaging techniques revealed changes in fractional anisotropy and mean diffusivity in magnetic resonance imaging and higher 11C-DTBZ binding in positron-emission tomography scans, associated with grafts. Postmortem analysis showed that transplanted DAN survived over ten months in the putamen, without developing tumors, in the immunosuppressed NHPs. These results indicate that cell replacement therapy with hESCs-derived DAN causes long-term biochemical, anatomical, and physiological improvements in this model of PD.

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Adolfo Lopez-Ornelas, Itzel Escobedo-Avila, Gabriel Ramirez-Garcia, Rolando Lara-Rodarte, Cesar Melendez-Ramirez, Beetsi Urrieta-Chavez, Tonatiuh Barrios-Garcia, Veronica Caceres-Chavez, Xochitl Flores-Ponce, Francia Carmona, Carlos A Reynoso, Carlos Aguilar, Nora E Kerik, Luisa Rocha, Leticia Verdugo-Diaz, Victor Trevino, Jose Bargas, Veronica Ramos-Mejia, Juan Fernandez-Ruiz, Aurelio Campos-Romo, Ivan Velasco. 2020-07-11. Human embryonic stem cells-derived dopaminergic neurons transplanted in parkinsonian monkeys recover dopamine levels and motor behavior. https://doi.org/10.1101/2020.07.08.192591

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