Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…C: cyclosporine; CPA: cyclosporine/prednisone/azathioprine; Put: putamen; CdN: caudate nucleus; NAcc: nucleus accumbens; SN: substantia nigra; cyno: cynomolgus; AFG: African green monkey. Pernaute et al, 2005;Takagi et al, 2005;Kriks et al, 2011;Hayashi et al, 2013;Morizane et al, 2013) or measurement of the binding potential of 11 C-2β-carbomethoxy-3β-(4-fluorophenyl)tropane ( 11 C-CFT) at the dopamine nerve terminals (Hayashi et al, 2013;Hallett et al, 2015). The graft content is occasionally further analyzed through staining for GIRK2 and CALBINDIN to highlight the presence of A9 and A10 DA neurons respectively (Kikuchi et al, 2011;Kriks et al, 2011;Sundberg et al, 2013;Wang et al, 2015).…”

“…Accordingly, the content of the grafts from PSC-derived DA neurons is variable, with a usually high proportion of MAP2+ neurons, from which only a small proportion expresses TH (Takagi et al, 2005;Doi et al, 2012;Emborg et al, 2013a). A9 type DA neurons generally maintained their original A9 characteristics upon grafting (Hayashi et al, 2013;Wang et al, 2015). Nonnegligible amounts of other types of neurons (GABA+ and SEROTONIN+), GFAP+ astrocytes and MBP+ oligodendrocytes are also found in the grafts (Emborg et al, 2013a).…”

“…In contrast, their capacity to reinnervate distant targets seems rather limited in the NHP brain, with TH+ fibers extending only a few millimeters into the host Collier et al, 2002;Takagi et al, 2005;Kriks et al, 2011;Emborg et al, 2013a), although this parameter was often not extensively documented Sanchez-Pernaute et al, 2005;Takagi et al, 2005;Kikuchi et al, 2011;Daadi et al, 2012;Doi et al, 2012;Hayashi et al, 2013;Morizane et al, 2013;Sundberg et al, 2013;Hallett et al, 2015;Wang et al, 2015). fVM grafts performed either in the CdN or in the putamen induce increased TH innervation of the non-grafted ipsilateral nucleus , suggesting that they could potentially extend long neurites.…”

Stem cells in Parkinson’s disease: an update

“…Long term survival of transplanted cells and restoration of motor function was also found after autologous engraftment of A9 DA-ergic neuron-like cells induced from mesenchymal stem cells (MSCs) in affected portions of striatum in hemiparkinsonian macaques [77]. For seven months DAT expression remained above baseline levels whereas for nine months cells positive for DAT and other A9 DA-ergic neuron markers were consistently demonstrated in the engrafted striatum [77]. Noninvasive intranasal (IN) delivery of MSCs to the brains of unilateral 6-OHDA-lesioned rats resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord [78].…”

“…Intrastriatal transplantation of these GDNF-treated cells in a 6-OHDA rat model of PD, resulted in integration of TH+ and DAT+ cells and functional recovery in motor behaviors in apomorphine-induced rotational behavior and adjusting step and paw-reaching tests [76]. Long term survival of transplanted cells and restoration of motor function was also found after autologous engraftment of A9 DA-ergic neuron-like cells induced from mesenchymal stem cells (MSCs) in affected portions of striatum in hemiparkinsonian macaques [77]. For seven months DAT expression remained above baseline levels whereas for nine months cells positive for DAT and other A9 DA-ergic neuron markers were consistently demonstrated in the engrafted striatum [77].…”