Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration

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

“…A previous study in which MSC-DP cells were engrafted into rodents consistently showed no evidence of tumorigenicity during a 14-week period (20). Schwann cells derived from MSCs also showed no tumorigenicity during a 1-year observation period in our previous study in primates (18). The differentiation technique for converting naive MSCs to MSC-DP cells involved NICD gene introduction by transfection of a plasmid gene but not by retrovirus-or lentivirus-mediated gene transfer, which is known to modify the nuclear genome.…”

“…Third, immunohistochemical analysis at 9 months confirmed the increase of DAT + /TH + /GIRK2 + cells and the TH + axon terminals in the engrafted striatum. Fourth, no tumorigenicity was suspected by peripheral blood tests, blood tumor markers, 18 F-FDG PET scans, and histology. Therefore, MSC-DP cells are likely to be nontumorigenic and able to remain in the transplanted region until at least 9 months after engraftment, although not in large quantities, thereby modestly restoring dopaminergic function and motor behaviors in vivo.…”

“…In our case, the TH + /DAT + /GIRK2 + cells were located only in an area near the engrafted area in the dorsal striatum ( Figure 5), and the number of the cells was larger than that in sham and nonaffected striata ( Figure 6, C and E). Second, regarding PET ligands, a well-known ligand for DA, 18 F-DOPA was not used in this study, because it is a metabolic ligand for amino acids and may reflect not only dopamine turnover in dopaminergic neurons, but also uptake of amino acid precursors in tumors (54) or inflammation (55). Therefore, 11 C-CFT was carefully chosen as an in vivo surrogate marker for tracking MSC-DP cells, because it is a highly specific ligand for DAT, which is specif-ically expressed in dopaminergic neurons and was confirmed to be present in the current MSC-DP cells in vitro.…”

“…We also performed 18 F-FDG PET to assess any tumorigenic changes in the grafted area using a previously described method (18). After induction of anesthesia, we injected 185 MBq of 18 F-FDG and scanned the head region for a period from 40 to 60 minutes after injection.…”

“…Recently, it was shown that MSCs could be artificially directed to differentiate into several specialized cell types, including those in nervous tissues (18)(19)(20)(21). Previously, we reported that dopamine-producing cells could be induced from MSCs (MSC-DP cells) by introduction of a Notch1 intracellular domain-containing (NICD-containing) plasmid, followed by cytokine stimulation with bFGF, forskolin, ciliary neurotrophic factor (CNTF), and glial cell linederived neurotrophic factor (GDNF) (20,21).…”