Mesenchymal Stem Cell Transplantation Attenuates Brain Injury After Neonatal Stroke

Abstract

Background and Purpose Brain injury caused by stroke is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. Mesenchymal stem cells (MSC) have been shown to improve outcome after neonatal hypoxic-ischemic brain injury mainly by secretion of growth factors stimulating repair processes. We investigated whether MSC-treatment improves recovery after neonatal stroke and whether MSC overexpressing brain-derived neurotrophic factor (MSC-BDNF) further enhances recovery. Methods We performed 1.5-hour transient middle cerebral artery occlusion (MCAO) in 10-day-old rats. Three days after reperfusion, pups with evidence of injury by diffusion-weighted MRI were treated intranasally with MSC, MSC-BDNF or vehicle. To determine the effect of MSC-treatment, brain damage, sensorimotor function and cerebral cell proliferation were analysed. Results Intranasal delivery of MSC- and MSC-BDNF significantly reduced infarct size and grey matter loss in comparison to vehicle-treated rats without any significant difference between MSC- and MSC-BDNF-treatment. Treatment with MSC-BDNF significantly reduced white matter loss with no significant difference between MSC- and MSC-BDNF-treatment. Motor deficits were also improved by MSC-treatment when compared to vehicle treated rats. MSC-BDNF-treatment resulted in an additional significant improvement of motor deficits 14 days post-MCAO, but there was no significant difference between MSC or MSC-BDNF 28 days post-MCAO. Furthermore, treatment with either MSC or MSC-BDNF induced long lasting cell proliferation in the ischemic hemisphere. Conclusions Intranasal administration of MSC after neonatal stroke is a promising therapy for treatment of neonatal stroke. In this experimental paradigm MSC and BNDF-hypersecreting-MSC are equally effective in reducing ischemic brain damage.

Mechanisms of Perinatal Arterial Ischemic Stroke

“…As in experimental adult stroke studies, transplantation of stem cells and cell-based therapies, including mesenchymal stem/ progenitor cells, provide promising results in animal models of neonatal brain injury [182][183][184][185] but several aspects of stem-cell therapy including stem-cell origin, number and location of the transplanted cells, and timing of transplantation after injury still need to be refined before considering their use in humans. Another aspect that has yet to be understood is whether engrafted cells themselves enhance the repair by replacement of dead neurons or by stimulating the microenvironment (gene expression of growth factors and inflammatory molecules), which, in turn, permits remodeling and improvement of neurologic function.…”

Intranasal delivery of bone marrow stromal cells to spinal cord lesions

“…Until now, the migration of intranasally administered MSCs to a lesion and the efficacy of this treatment have been reported for a cerebral infarction model in mice, 12,22 an experimental autoimmune encephalomyelitis model in mice, 13 and a Parkinson's disease model in rats. 8 Surpris ingly, the cells have been observed in the spinal cord as well as in the cortex, cerebellum, and brainstem 4 hours after the intranasal administration in the rat model of Par kinson's disease.…”

“…Recently, the intranasal administra tion of BMSCs into lesioned brains of rodents has been reported. 5,9,12,13,22,24 After their administration by simple drops into the nostrils, BMSCs are thought to migrate into the brains through the olfactory nerve route or trigeminal ganglion route. From the point of view of minimizing in vasiveness, the intranasal route is thought to be the least invasive of all the routes mentioned above.…”

Hypoxic and ischemic effects on gene and protein expression levels of paracrine factors by human olfactory mucosa mesenchymal-like stem cells

“…The data suggest that the low serum and oxygen conditions present during the ischemia found after brain ischemia may have significant effects on the secretory function of MSCs and the role they play in preventing the loss of cerebral function after cerebral infarction. 31 The particular changes observed depend on the specific paracrine factors that were studied. Changes in mRNA often were in line with changes in secretion, and there were few exceptions.…”