Abstract
BackgroundAdipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. The current study aimed to explore the contribution of miRNAs in ADSC-EVs to the treatment of cerebral ischemia.MethodsAfter the intravenous injection of ADSC-EVs, therapeutic efficacy was evaluated by neurobehavioral tests and brain atrophy volume. The polarization of microglia was assessed by immunostaining and qPCR. We further performed miRNA sequencing of ADSC-EVs and analyzed the relationship between the upregulated miRNAs in ADSC-EVs and microglial polarization-related proteins using Ingenuity Pathway Analysis (IPA).ResultsThe results showed that ADSC-EVs reduced brain atrophy volume, improved neuromotor and cognitive functions after mouse ischemic stroke. The loss of oligodendrocytes was attenuated after ADSC-EVs injection. The number of blood vessels, as well as newly proliferated endothelial cells in the peri-ischemia area were higher in the ADSC-EVs treated group than that in the PBS group. In addition, ADSC-EVs regulated the polarization of microglia, resulting in increased repair-promoting M2 phenotype and decreased pro-inflammatory M1 phenotype. Finally, STAT1 and PTEN were highlighted as two downstream targets of up-regulated miRNAs in ADSC-EVs among 85 microglia/macrophage polarization related proteins by IPA. The inhibition of STAT1 and PTEN by ADSC-EVs were confirmed in cultured microglia.ConclusionsIn summary, ADSC-EVs reduced ischemic brain injury, which was associated with the regulation of microglial polarization. miRNAs in ADSC-EVs partly contributed to their function in regulating microglial polarization by targeting PTEN and STAT1.
Highlights
Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood
We aim to investigate whether ADSC-EVs regulate the polarization of microglia and contribute to neurological recovery after ischemic stroke
Isolation and identification of ADSC‐EVs To obtain allogeneic ADSC-EVs, we first obtained subcutaneous white fat tissue (WAT) from the bilateral inguinal region of 6-week-old ICR male mice and isolated the primary ADSCs according to a method described previously [37]
Summary
Adipose-derived stem cells (ADSCs) and their extracellular vesicles (EVs) have therapeutic potential in ischemic brain injury, but the underlying mechanism is poorly understood. Hu et al Stem Cell Research & Therapy (2022) 13:21 These treatments usually have a narrow therapeutic window [3]. In the early phase of acute brain ischemia, an anti-inflammatory M2 microglia phenotype increases from 1 to 3 days and peaks by 3 to 5 days post ischemic brain injury. A pro-inflammatory M1 microglia phenotype gradually increases over time from day 3 onward and maintain elevated for at least 14 days after ischemic stroke [6]. The dynamic polarization of microglia and their interaction with neurons, astrocytes, and oligodendrocytes play important roles in the pathological process of cerebral ischemia. Shifting microglial polarization to M2 phenotype has been proposed to be a new therapeutic strategy for cerebral ischemia [14, 15]
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