Better Outcomes with Intranigral versus Intrastriatal Cell Transplantation: Relevance for Parkinson’s Disease

Abstract

Intrastriatal embryonic ventral mesencephalon grafts have been shown to integrate, survive, and reinnervate the host striatum in clinical settings and in animal models of Parkinson’s disease. However, this ectopic location does not restore the physiological loops of the nigrostriatal pathway and promotes only moderate behavioral benefits. Here, we performed a direct comparison of the potential benefits of intranigral versus intrastriatal grafts in animal models of Parkinson’s disease. We report that intranigral grafts promoted better survival of dopaminergic neurons and that only intranigral grafts induced recovery of fine motor skills and normalized cortico-striatal responses. The increase in the number of toxic activated glial cells in host tissue surrounding the intrastriatal graft, as well as within the graft, may be one of the causes of the increased cell death observed in the intrastriatal graft. Homotopic localization of the graft and the subsequent physiological cell rewiring of the basal ganglia may be a key factor in successful and beneficial cell transplantation procedures.

Host-to-graft Propagation of α-synuclein in a Mouse Model of Parkinson’s Disease: Intranigral Versus Intrastriatal Transplantation

“…In line with this hypothesis, we recently demonstrated that mouse fVM cells grafted into the striatum presented a rather proinflammatory activation profile of glial cells compared to the intranigral grafts, which presented a rather anti-inflammatory activation profile. 16 This differential inflammatory response could be responsible of the preferential accumulation of α-syn into striatal grafts as it is known that microglia and astrocytes contribute to the propagation of α-syn. [41][42][43][44][45] In conclusion, our study is the first to compare side-byside the propagation of α-syn from the host brain to nigral or striatal grafts.…”

“…This result is in line with a previous study showing that intranigral grafts show a better anatomical and functional integration than intrastriatal grafts. 16 In this study, we used fetal neurons as a cell source for transplantation. It would be interesting to repeat this study using induced pluripotent stem cells-derived DA neurons as clinical trial using intrastriatal transplantation of human-induced pluripotent stem cells-derived DA precursor cells is currently underway.…”

“…Five wk after the viral vector injection, the transplantation procedure was performed according to a previously described technique. 16 To facilitate the identification of transplanted cells into the host brain, donor fVM tissue was isolated from transgenic mice embryo overexpressing green fluorescent protein (GFP) under β-actin promotor. 30 Briefly, fVM tissue was removed from embryos at stage E12.5, collected in basic medium (0.6% glucose in saline), and dissociated into cell suspension with fire-polished Pasteur pipette.…”

“…[10][11][12][13][14][15] Additionally, we recently showed that intranigral transplantation of mouse DA progenitors obtained from fVM into 6-hydroxydopamine-lesioned mice led to better neuroanatomical and functional integration of grafted DA neurons than intrastriatal transplantation. 16 These findings led to the assumption that SNpc represents a more suitable site for graft survival and integration than the striatum.…”

Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson’s Disease Animal Model

“…hESCs and hiPSCs are increasingly recognized for their potential in PD cell replacement therapies via transplantation into the striatum [ 30 ], and SNpc, in this last specific case to restore the nigrostriatal pathway in a more physiological manner [ 31 , 32 , 33 , 34 , 35 , 36 ]. Grafting stem cells at various maturation stages, including as floor-plate progenitors, has shown promise due to their high dopaminergic differentiation potential [ 36 , 37 ].…”