Background and Purpose— Retinal ischemia is a major cause of visual impairment in stroke patients, but our incomplete understanding of its pathology may contribute to a lack of effective treatment. Here, we investigated the role of mitochondrial dysfunction in retinal ischemia and probed the potential of mesenchymal stem cells (MSCs) in mitochondrial repair under such pathological condition. Methods— In vivo, rats were subjected to middle cerebral artery occlusion then randomly treated with intravenous MSCs or vehicle. Laser Doppler was used to evaluate the blood flow in the brain and the eye, while immunohistochemical staining assessed cellular degeneration at days 3 and 14 poststroke. In vitro, retinal pigmented epithelium cells were exposed to either oxygen-glucose deprivation or oxygen-glucose deprivation and coculture with MSCs, and subsequently, cell death and mitochondrial function were examined immunocytochemically and with Seahorse analyzer, respectively. Results— Middle cerebral artery occlusion significantly reduced blood flow in the brain and the eye accompanied by mitochondrial dysfunction and ganglion cell death at days 3 and 14 poststroke. Intravenous MSCs elicited mitochondrial repair and improved ganglion cell survival at day 14 poststroke. Oxygen-glucose deprivation similarly induced mitochondrial dysfunction and cell death in retinal pigmented epithelium cells; coculture with MSCs restored mitochondrial respiration, mitochondrial network morphology, and mitochondrial dynamics, which likely attenuated oxygen-glucose deprivation-mediated retinal pigmented epithelium cell death. Conclusions— Retinal ischemia is closely associated with mitochondrial dysfunction, which can be remedied by stem cell-mediated mitochondrial repair.
Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.
Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.
Accumulating evidence has demonstrated that menstrual blood stands as a viable source of stem cells. Menstrual blood-derived stem cells (MenSCs) are morphologically and functionally similar to cells directly extracted from the endometrium, and present dual expression of mesenchymal and embryonic cell markers, thus becoming interesting tools for regenerative medicine. Functional reports show higher proliferative and self-renewal capacities than bone marrow-derived stem cells, as well as successful differentiation into hepatocyte-like cells, glial-like cells, endometrial stroma-like cells, among others. Moreover, menstrual blood stem cells may be used with increased efficiency in reprogramming techniques for induced Pluripotent Stem cell (iPS) generation. Experimental studies have shown successful treatment of stroke, colitis, limb ischemia, coronary disease, Duchenne's muscular atrophy and streptozotocin-induced type 1 diabetes animal models with MenSCs. As we envision an off-the-shelf product for cell therapy, cryopreserved MenSCs appear as a feasible clinical product. Clinical applications, although still very limited, have great potential and ongoing studies should be disclosed in the near future.
Stroke is a major cause of death and disability in the United States and around the world with limited therapeutic option. Here, we discuss the critical role of mitochondria in stem cell-mediated rescue of stroke brain by highlighting the concept that deleting the mitochondria from stem cells abolishes the cells’ regenerative potency. The application of innovative approaches entailing generation of mitochondria-voided stem cells as well as pharmacological inhibition of mitochondrial function may elucidate the mechanism underlying transfer of healthy mitochondria to ischemic cells, thereby providing key insights in the pathology and treatment of stroke and other brain disorders plagued with mitochondrial dysfunctions.
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