Combined cell-based therapy strategies for the treatment of Parkinson's disease:focus on mesenchymal stromal cells

Parkinson’s disease is a neurodegenerative condition characterized by motor impairments caused by the selective loss of dopaminergic neurons in the substantia nigra.Levodopa is an effective and well-tolerated dopamine replacement agent.However,levodopa provides only symptomatic improvements,without affecting the underlying pathology,and is associated with side effects after long-term use.Cell-based replacement is a promising strategy that offers the possibility to replace lost neurons in Parkinson’s disease treatment.Clinical studies of transplantation of human fetal ventral mesencephalic tissue have provided evidence that the grafted dopaminergic neurons can reinnervate the striatum,release dopamine,integrate into the host neural circuits,and improve motor functions.One of the limiting factors for cell therapy in Parkinson’s disease is the low survival rate of grafted dopaminergic cells.Different factors could cause cell death of dopaminergic neurons after grafting such as mechanical trauma,growth factor deprivation,hypoxia,and neuroinflammation.Neurotrophic factors play an essential role in the survival of grafted cells.However,direct,timely,and controllable delivery of neurotrophic factors into the brain faces important limitations.Different types of cells secrete neurotrophic factors constitutively and co-transplantation of these cells with dopaminergic neurons represents a feasible strategy to increase neuronal survival.In this review,we provide a general overview of the pioneering studies on cell transplantation developed in patients and animal models of Parkinson’s disease,with a focus on neurotrophic factor-secreting cells,with a particular interest in mesenchymal stromal cells;that co-implanted with dopaminergic neurons would serve as a strategy to increase cell survival and improve graft outcomes.

Neurotrophic factors increase tyrosine hydroxylase immunoreactive cell density of fetal mesencephalic cells

Objective To hibernate fetal ventral mesencephalic tegmental (VMT) cells from Spraque Dawley rats E 15 for 5 days at 4℃ in either hibernation media (HM) or in conditioned hibernation media (CHM) supplemented with trophic factors such as epidermal growth factor (EGF 200 ng/ml), basic fibroblast growth factor (bFGF 100 ng/ml), recombinant human brain derived neurotrophic factor (rhBDNF 20 μg/ml), recombinant human glial cell derived neurotrophic factor (rhGDNF 20 μg/ml), fetal calf serum (FCS 9%), or human placental cord serum (HPCS 10%). Methods The percent of cell viability and the density of tyrosine hydroxylase immunoreactive (THir) cells in fetal striatal VMT co culture were determined. Results The viability of fetal striatal cells (0.8± 0.104) was slightly higher than that of fetal VMT cells (0.7±0.072) at 0 time point (F 17,1 =4.677; P= 0.045). After 5 days of hibernation, the viability of fetal VMT cells reduced by 30% (F 7,1 =88.493; P<0.001) in HM. However, THir cell density reduced by more than 90% as compared to the freshly harvested VMT cells (F 7,1 =179.944; P<0.001). CHM with HPCS, bFGF, EGF, BDNF, and GDNF showed higher THir cell density than that of HM or CHM supplemented with FCS (P<0.001). Conclusion Supplementation of appropriate trophic factors for hibernated fetal VMT cells promotes cell viability and the subsequent expression of THir cell density.