Human placental mesenchymal stem cells improve stroke outcomes via extracellular vesicles-mediated preservation of cerebral blood flow

Abstract

Background Besides long-term trans-differentiation into neural cells, benefits of stem cell therapy (SCT) in ischemic stroke may include secretion of protective factors, which partly reflects extracellular vesicle (EVs) released by stem cell. However, the mechanism(s) by which stem cells/EVs limit stroke injury have yet to be fully defined. Methods We evaluated the protection effect of human placenta mesenchymal stem cells (hPMSC) as a potential form of SCT in experimental ischemic stroke ‘transient middle cerebral artery occusion (MCAO)/reperfusion’ mice model. Findings We found for the first time that intraperitoneal administration of hPMSCs or intravenous hPMSC-derived EVs, given at the time of reperfusion, significantly protected the ipsilateral hemisphere from ischemic injury. This protection was associated with significant restoration of normal blood flow to the post-MCAO brain. More importantly, EVs derived from hPMSC promote paracrine-based protection of SCT in the MCAO model in a cholesterol/lipid-dependent manner. Interpretation Together, our results demonstrated beneficial effects of hPMSC/EVs in experimental stroke models which could permit the rapid “translation” of these cells into clinical trials in the near-term.

Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke

“…A number of studies have compared MSCs derived from the umbilical cord, dental pulp, bone marrow, and adipose tissue and found that MSCs derived from the umbilical cord have stronger proliferation activity [113,114]. Studies have shown that UC-MSCs and placenta-derived MSCs (PL-MSCs) can alleviate neurological deficits after cerebral ischemia in rats, and their potential mechanisms are similar to those described above [96,[115][116][117]. It is worth noting that the data of Liao et al showed that after transplantation of human UC-MSCs, more than 90% of the blood vessels around the cerebral ischemic area contained transplanted mesenchymal stem cells, which were integrated into the blood vessels and partially differentiated into endothelial cells [115].…”

“…An experiment in rats with hypoxic ischemic encephalopathy (HIE) model showed that the number of MSCs injected intraperitoneally homed to the ischemic area was less than that injected intravenously [135]. However, Barzegar et al showed that intraperitoneal injection of MSCs showed a high survival rate [116]. These authors further demonstrated that intraperitoneal injection of MSCs into MCAO mice also showed an effective neuroprotective effect, which may be related to the significant recovery of cerebral blood flow after administration [116].…”

“…However, Barzegar et al showed that intraperitoneal injection of MSCs showed a high survival rate [116]. These authors further demonstrated that intraperitoneal injection of MSCs into MCAO mice also showed an effective neuroprotective effect, which may be related to the significant recovery of cerebral blood flow after administration [116].…”

“…Cholesterol, as an important component of EVs, participates in the production, secretion, and functional regulation of EVs [155]. Barzegar Stem Cells International transplantation was also significantly improved [116]. When 1 × 10 5 human PL-MSCs treated with cholesterol lipid were intravenously injected into mice after MCAO induction for 1 hour, the researchers found that they could reduce the infarct size and restore neurological function, while the same low dose of common human PL-MSCs did not show any protective effect [116].…”

“…Barzegar Stem Cells International transplantation was also significantly improved [116]. When 1 × 10 5 human PL-MSCs treated with cholesterol lipid were intravenously injected into mice after MCAO induction for 1 hour, the researchers found that they could reduce the infarct size and restore neurological function, while the same low dose of common human PL-MSCs did not show any protective effect [116]. These evidences suggest that pretreatment of MSCs with cholesterol lipids can improve the efficacy of MSCs in the treatment of IS by enhancing the release and survival ability of EVs.…”