Hypoxia-Preconditioned Bone Marrow Mesenchymal Stem Cells Improved Cerebral Collateral Circulation and Stroke Outcome in Mice

Abstract

BACKGROUND: Adequate collateral circulation can remarkably improve patient prognoses for patients experiencing ischemic stroke. Hypoxic preconditioning enhances the regenerative properties of bone marrow mesenchymal stem cells (BMSCs). Rabep2 (RAB GTPase binding effector protein 2) is a key protein in collateral remodeling. We investigated whether BMSCs and hypoxia-preconditioned BMSCs (H-BMSCs) augment collateral circulation poststroke, particularly through Rabep2 regulation. METHODS: BMSCs or H-BMSCs (1×10 6 ) were delivered intranasally in ischemic mice with distal middle cerebral artery occlusion at 6 hours poststroke. Two-photon microscopic imaging and vessel painting methods were used to analyze collateral remodeling. Blood flow, vascular density, infarct volume, and gait analysis were assessed to evaluate poststroke outcomes. Expressions of proangiogenic marker VEGF (vascular endothelial growth factor) and Rabep2 were determined by Western blotting. Western blot, EdU incorporation, and tube formation assays were conducted on cultured endothelial cells treated with BMSCs. RESULTS: BMSCs were more effectively transplanted in the ischemic brain after hypoxic preconditioning. The ipsilateral collateral diameter was increased by BMSCs and strengthened by H-BMSCs ( P <0.05). BMSCs increased peri-infarct blood flow and vascular density and reduced infarct volume, gait deficits ( P <0.05), and furthermore by H-BMSCs ( P <0.05). VEGF and Rabep2 protein expression was increased by BMSCs ( P <0.05), which was enhanced by preconditioning ( P <0.01). Additionally, BMSCs increased Rabep2 expression, proliferation, and tube formation of endothelial cells in vitro ( P <0.05). H-BMSCs enhanced these effects ( P <0.05), which were annulled by Rabep2 knockdown. CONCLUSIONS: BMSCs increased collateral circulation and improved poststroke outcomes, through the upregulation of Rabep2. These effects were enhanced by hypoxic preconditioning.

Neural Stem Cell-Derived Small Extracellular Vesicles: key Players in Ischemic Stroke Therapy – A Comprehensive Literature Review

“… 53 , 54 Transplanted stem cells can induce angiogenesis by releasing vascular endothelial growth factor, eliciting anti-inflammatory responses and other benefits. 55 The comprehensive array of ways NSCs operate in managing ischemic stroke indicates that the restoration and healing of neural networks in the brain following such an event are facilitated through various means. Because of the low survival rate of transplanted stem cells, stem cell therapy acts primarily through time-limited paracrine mechanisms.…”

Molecular Mechanisms of Neuroprotection after the Intermittent Exposures of Hypercapnic Hypoxia

“…It is known that normobaric hypoxia activates synthetic and proliferative activity in cells [103], and a number of recent experimental studies have shown that hypoxic preconditioning enhances the proliferative activity of mesenchymal stem cells [104,105], as well as neural stem cells [106].…”

Bibliometric Analysis of Stem Cells in Ischemic Stroke (2001-2022): Trends, Hotspots and Prospects

“…Both in vivo and in vitro experiments have demonstrated that MSCs regulate the pathological processes of ischemic stroke via multiple targets. Several studies showed that MSCs enhanced collateral circulation by upregulating proteins involved in collateral remodeling and rescued damaged neurons by mitochondrial transfer and immunomodulatory effect [69,70]. MSCs are also known to facilitate axon regeneration via modulating the functioning of astrocytes and microglia [71].…”