Embryonic substantia nigra grafts in the mesencephalon send neurites to the host striatum in non‐human primate after overexpression of GDNF

Abstract

In spite of partial success in treating Parkinson's disease using ectopically placed grafts of dopamineproducing cells, restoration of the original neuroanatomical circuits, if possible, might work better. Previous evidence of normal anatomic projections from ventral mesencephalic (VM) grafts placed in the substantia nigra (SN) has been limited to neonatal rodents and double grafting or bridging procedures. This study attempted to determine whether injection of a potent growth promoting factor, glial cell line-derived neurotrophic factor (GDNF), into the target regions or placement of fetal striatal co-grafts in the nigrostriatal pathway might elicit neuritic outgrowth to the caudate nucleus. Four adult St. Kitts green monkeys received embryonic VM grafts into the rostral mesencephalon near the host substantia nigra, and injections of AAV2/GDNF or EIAV/GDNF into the caudate. Three adult monkeys were co-grafted with fetal VM tissue near the substantia nigra and fetal striatal grafts (STR) 2.5 mm rostral in the nigrostriatal pathway. Before sacrifice, the striatal target regions were injected with the retrograde tracer fluorogold (FG). FG label was found in tyrosine hydroxylaselabeled neurons in VM grafts in the SN of only those monkeys that received AAV2/GDNF vector injections into the ipsilateral striatum. All monkeys showed FG labeling in the host substantia nigra when FG labeling was injected on the same side. These data show that grafted dopaminergic neurons can extend neurites to a distant target releasing an elevated concentration of GDNF, and suggest that grafted neurons can be placed into appropriate loci for potential tract reconstruction.

Cell Transplantation and Gene Therapy in Parkinson's Disease

“…Interestingly, the target‐directed outgrowth and functional benefit reported by Thompson and colleagues was further enhanced by overexpression of recombinant adeno‐associated virus (rAAV)‐ GDNF gene therapy delivered to the striatum 228. In support, recent work from Redmond and colleagues demonstrated that rAAV2‐mediated gene transfer of GDNF to the striatum of MPTP‐treated monkeys resulted in a marked increase in survival of primary fetal VM DA‐precursor cells by several‐fold and elicited directional outgrowth of axons 232,233. The combined results support the proof‐of‐concept of cell transplantation combined with gene therapy for nigrostriatal reconstruction in PD.…”

Cell Therapy from Bench to Bedside Translation in CNS Neurorestoratology Era

“…Functional recovery could be mediated by neurotrophic support, new synaptic circuit elaboration, and enhancement of the stroke-induced neuroplasticity (74). Recent findings of transplanted embryonic dopamine (DA) neurons into the substantia nigra (SN) indicate that DA neurons could extend neurites towards a desired target through the brain stem and caudal diencephalon to reconstruct the neural circuitry from grafted neurons in the host (315,355). Application of stem cells for neuroreplacement therapy is therefore no longer science fiction—it is science fact (367).…”

Long distance directional growth of dopaminergic axons along pathways of netrin-1 and GDNF

“…GDNF has been used successfully to increase the survival of fetal dopaminergic cell transplants in the 6-OHDA-lesioned rat striatum (Rosenblad et al, 1996; Yurek, 1998). Viral mediated over-expression of GDNF within the striatum establishes a gradient that induces axon growth into the striatum from dopaminergic neurons within nigral transplants in both mouse and non-human primate models (Thompson et al, 2009; Kordower et al, 2000; Redmond et al, 2009). These studies were performed in partially lesioned animals, and in the mouse model complete lesions showed no growth of transplanted axons toward the striatum, indicating surviving endogenous dopaminergic axons might act as a growth supportive scaffold.…”