MicroRNA‐210 Promotes Accumulation of Neural Precursor Cells Around Ischemic Foci After Cerebral Ischemia by Regulating the SOCS1–STAT3–VEGF‐C Pathway

Abstract

BackgroundNeural precursor cell (NPC) migration toward lesions is key for neurological functional recovery. The neovasculature plays an important role in guiding NPC migration. MicroRNA‐210 (miR‐210) promotes angiogenesis and neurogenesis in the subventricular zone and hippocampus after cerebral ischemia; however, whether miR‐210 regulates NPC migration and the underlying mechanism is still unclear. This study investigated the role of miR‐210 in NPC migration.Methods and ResultsNeovascularization and NPC accumulation was detected around ischemic foci in a mouse model of middle cerebral artery occlusion (MCAO) and reperfusion. Bone marrow–derived endothelial progenitor cells (EPCs) were found to participate in neovascularization. miR‐210 was markedly upregulated after focal cerebral ischemia/reperfusion. Overexpressed miR‐210 enhanced neovascularization and NPC accumulation around the ischemic lesion and vice versa, strongly suggesting that miR‐210 might be involved in neovascularization and NPC accumulation after focal cerebral ischemia/reperfusion. In vitro experiments were conducted to explore the underlying mechanism. The transwell assay showed that EPCs facilitated NPC migration, which was further promoted by miR‐210 overexpression in EPCs. In addition, miR‐210 facilitated VEGF‐C (vascular endothelial growth factor C) expression both in vitro and in vivo. Moreover, the luciferase reporter assay demonstrated that miR‐210 directly targeted the 3′ untranslated region of SOCS1 (suppressor of cytokine signaling 1), and miR‐210 overexpression in HEK293 cells or EPCs decreased SOCS1 and increased STAT3 (signal transducer and activator of transcription 3) and VEGF‐C expression. When EPCs were simultaneously transfected with miR‐210 mimics and SOCS1, the expression of STAT3 and VEGF‐C was reversed.ConclusionsmiR‐210 promoted neovascularization and NPC migration via the SOCS1–STAT3–VEGF‐C pathway.

Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia

“…These findings are in agreement with studies on the pro-angiogenic role of miR-210 observed in vitro [15,[31][32][33], as well as in miR-210 overexpression studies in mouse models of heart [20][21][22][23], limb [26], and brain ischemia [24,25,34]. Also concordant are studies showing that cord blood-derived cells expressing miR-210 display an increased potential in stimulating angiogenesis upon transplantation Taken together, these results indicate that miR-210 plays a pro-angiogenic role in vivo also in the absence of ischemic injury.…”

“…Moreover, the role played by miR-210 might be highly context-dependent [6,7]. In different experimental settings, miR-210 has been shown to stimulate the secretion of pro-angiogenic factors, such as VEGF and FGF2 [23,25,36,[38][39][40], which may play a role in the vascular regeneration process also in the context of hindlimb ischemia. Finally, it is worth noting that miR-210 can be secreted into exosomes and, in this way, transferred from cell to cell, further complicating the scenario [20,26,41].…”

“…This evidence prompted studies aimed at demonstrating the ability of miR-210 to stimulate angiogenesis in ischemic disease models. Driven by a translational purpose, in these investigations, an overexpression strategy in the ischemic tissue was adopted, showing miR-210 s ability to stimulate angiogenesis in heart [20][21][22][23], brain [24,25] and limb ischemia [26]. However, a combination of gain-and loss-of-function approaches is instrumental in providing a clear picture of miR-210 implication in the pathogenetic mechanisms underpinning the ischemia-induced angiogenic response.…”

Hypoxia-challenged MSC-derived exosomes deliver miR-210 to attenuate post-infarction cardiac apoptosis

“…These results are in accordance with several studies suggesting that miR-210 has a protective function in cardiovascular disease through several mechanisms including SOCS1-STAT3-VEGF-C signaling [30]. Consistent with this finding, blocking the activity of nSMase2 lead to a reduction in miR-210 and abrogated any cardio-protective actions.…”

Human embryonic derived neural progenitor cells improves neurological scores following brain ischemia/ reperfusion: Modulation of blood and brain tissue MicroRNA-210

“…17 In ischemic condition, mir-210 plays role as a proangiogenic factor and involves in cell-cycle regulation, DNA damage reconstruction, and neural tissue restoration. [17][18][19]…”