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

Abstract

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.

Protection and Repair of the Nigrostriatal Pathway with Stem-Cell-Derived Carotid Body Glomus Cell Transplants in Chronic MPTP Parkinsonian Model

“…Stem-cell-derived dopaminergic and GDNF-producing glomus cells represent a new therapeutic option to be considered in cell therapy in PD. These cells could be useful either for inducing neurotrophic protection and the stimulation of damaged SNpc neurons or for improving the survival and efficacy of hfVM transplants [ 9 , 44 , 45 ]. The neurotrophic potential of stem-cell-derived CB glomus cells could also be relevant for the treatment of other neurodegenerative diseases [ 46 , 47 ].…”

“…However, two double-blind controlled trials questioned the clinical efficacy of this procedure, and showed the appearance of dyskinesias in some grafted patients [ 6 , 7 ]. The lack of a clinical improvement and the side effects observed in the double-blind controlled trials were attributed to methodological issues, such as patient selection, hfVM tissue preparation and implantation and the immunosuppressive regime applied post-transplantation [ 8 , 9 ]. Recently, a new open-label study, where these methodological issues have been strictly standardized, was designed to re-evaluate the clinical efficacy of hfVM grafts [ 10 , 11 ].…”

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“…The articles were chosen from articles registered in the databases with the following keywords: Mental Health, Complementary Therapies, Parkinson's Disease, and Symptoms. [4][5][6][7] The articles were selected with the following inclusion criteria: studies published in English or Portuguese, with the main theme on Parkinson's disease. The exclusion criteria were incomplete studies, duplicated studies, or studies not related to the theme.…”

The cytosolic DNA‐sensing cGAS–STING pathway in neurodegenerative diseases

“…The main pathological change in PD is the degeneration and death of dopaminergic neurons in the substantia nigra area, which leads to a decrease in dopamine content in the ventral striatum and the dysfunction of motor regulation and cognitive impairment. Dopamine (DA), dopaminergic neuron cell death, oxidative stress, and neuroinflammation have been shown to play significant roles in the pathogenesis of PD 83,84 . The cGAS‐STING pathway is most likely to be activated during the progression of PD, as injured dopaminergic neurons can produce dsDNA.…”