Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model

Abstract

Parkinson disease (PD) is a neurodegenerative disorder characterized by loss of midbrain dopaminergic (DA) neurons. ES cells are currently the most promising donor cell source for cell-replacement therapy in PD. We previously described a strong neuralizing activity present on the surface of stromal cells, named stromal cell–derived inducing activity (SDIA). In this study, we generated neurospheres composed of neural progenitors from monkey ES cells, which are capable of producing large numbers of DA neurons. We demonstrated that FGF20, preferentially expressed in the substantia nigra, acts synergistically with FGF2 to increase the number of DA neurons in ES cell–derived neurospheres. We also analyzed the effect of transplantation of DA neurons generated from monkey ES cells into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–treated (MPTP-treated) monkeys, a primate model for PD. Behavioral studies and functional imaging revealed that the transplanted cells functioned as DA neurons and attenuated MPTP-induced neurological symptoms

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

“…We performed 11 C-CFT PET scanning to evaluate DAT expression in cynomolgus brains, as described previously (26,62). The tracer 11 C-CFT was prepared by a conventional method using 11 C-methyl-triflate (63) and a precursor, nor[methyl-11 C]2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane.…”

“…When rat and human MSC-DP cells were transplanted into the striata of PD model rats, integration of TH + and DAT + cells and functional recovery in motor behaviors were confirmed (20). Subsequent development of a spermine-pullulan-mediated reverse transfection method allowed us to induce MSC-DP cells more safely and efficiently than before from MSCs of macaque monkeys (21), an animal species frequently used for preclinical trials of PD (22)(23)(24)(25)(26)(27).…”

Transplantation of Human Neural Stem Cells Exerts Neuroprotection in a Rat Model of Parkinson's Disease

“…The infinite self-renewal capacity and neuronal differentiation potential of stem/progenitor cells make them an appealing donor graft source for cell therapy in PD (Snyder and Olanow, 2005;Sonntag et al, 2005). Candidate stem/progenitor cells for transplantation therapy in PD have been evaluated using several criteria, including their in vitro and in vivo phenotypic expression of the dopamine synthetic enzyme tyrosine hydroxylase (TH), as well as markers for dopamine transporter, their capacity to synthesize, release, take up, and catabolize dopamine, and also their ability to project axons to target nuclei such as the putamen (Arenas, 2002;Bjorklund et al, 2002;Lindvall and Bjorklund, 2004;Langston, 2005;Takagi et al, 2005). Although there is absent or minimal detection of fully mature neuronal differentiation of stem/progenitor cells into dopaminergic neurons, attenuation of parkinsonian symptoms have been observed, possibly as a result of the secretion of neurotrophic factors by the cells (Jung et al, 2004;Goldman, 2005;Rafuse et al, 2005).…”

Cell Therapeutics in Parkinson's Disease

“…So far, the most promising results have been obtained using embryonic stem (ES) cells [52][53][54][55][56][57][58][59][60][61][62] or therapeutically cloned ES cells [63]. The examples shown (Fig.…”