Overexpression of BRCA1 in Neural Stem Cells Enhances Cell Survival and Functional Recovery after Transplantation into Experimental Ischemic Stroke

Abstract

Transplantation of neural stem cells (NSCs) is a promising therapy for ischemic stroke. However, the effectiveness of this approach is limited by grafted cell death. Breast cancer susceptibility protein 1 (BRCA1) could suppress apoptosis in neural progenitors and modulate oxidative stress in neurons. In this study, we found that BRCA1 was upregulated by oxygen-glucose deprivation/reoxygenation (OGD/R). Overexpression of BRCA1 in NSCs reduced cell apoptosis and oxidative stress after OGD/R insult. The molecule overexpression also stimulated cellular proliferation in OGD/R NSCs and increased the survival rate of grafted cells. Further, the transplantation of BRCA1-transfected NSCs into mice with ischemic stroke increased brain-derived neurotropic factor and nerve growth factor expression in the brain and elicited neurological function improvement. In addition, we found that RING finger domain and BRCT domain of BRCA1 could physically interact with p53 in NSCs. The cross talk between BRCA1 RING finger domain and p53 was responsible for p53 ubiquitination and degradation. Our findings indicate that modification with BRCA1 could enhance the efficacy of NSCs transplantation in ischemic stroke.

Intracarotid Transplantation of Skin-Derived Precursor Schwann Cells Promotes Functional Recovery After Acute Ischemic Stroke in Rats

“…To align with this, we chose to infuse SKP-SCs through carotid artery catheter when cerebral perfusion was restored in MCAO rats. In regard to optimal time when stem cells should be transplanted, early application of cell therapy was found to effectively protect and repair neurons ( 26 ), and many studies have reported improvements of outcome with cell therapy given within 24 h after AIS ( 1 , 2 , 27 – 29 ). However, stem cell transplantation immediately after reperfusion has not been documented.…”

Oxygen-glucose deprivation in neurons: implications for cell transplantation therapies

“…Another strategy specifically designed to overcome OGD following neural transplantation is hypoxic conditioning of cells prior to grafting [91]. Short exposure to mild hypoxia leads to adaptation, resulting in a less severe response upon a second hypoxic insult (grafting), this is an attractive strategy as it can be combined with enhanced expression of pro-survival factors [92][93][94][95]. Briefly, this has been used to enhance the paracrine effect of bone marrow mesenchymal stem cells (BMSCs) on neurons.…”

“…The hypoxic conditioning enriched the BMSC secretome with vascular endothelial growth factor (VEGF) as a result of HIF-1α activity [92]. This method also yielded good results in NSCs when Breast cancer susceptibility protein 1 (BRCA1) was upregulated during OGD and following reperfusion [93]. The overexpression of this pro-survival protein was able to reduce apoptosis and the oxidative stress of grafted NSCs and provide better functional recovery [93].…”

“…This method also yielded good results in NSCs when Breast cancer susceptibility protein 1 (BRCA1) was upregulated during OGD and following reperfusion [93]. The overexpression of this pro-survival protein was able to reduce apoptosis and the oxidative stress of grafted NSCs and provide better functional recovery [93]. Similarly, the enhanced expression of brainderived neurotrophic factor (BDNF) in GABAergic hippocampal neurons resulted in better conditioning and survival upon a second OGD experiment [95].…”

Oxidative DNA Damage Signalling in Neural Stem Cells in Alzheimer’s Disease

“…Likewise, p21 controls the expansion of subependymal NSCs by limiting genetic defects upon the downregulation of the pluripotency-associated transcription factor SOX2 (Marqués-Torrejón et al, 2013). Another recent report demonstrated that overexpression of BRCA1 in NSCs promoted cell survival and functional recovery after transplantation in ischemic stroke [29]. In detail, Xu et al suggested that BRCA1 could suppress apoptosis in NPCs and modulate oxidative stress in neurons.…”