Exosomes from hypoxic pre-treated ADSCs attenuate acute ischemic stroke-induced brain injury via delivery of circ-Rps5 and promote M2 microglia/macrophage polarization.

Previous investigations have shown that exosome secretion from hypoxic pre-treated adipose-derived stem cells (ADSCs) affect ischemic injury treatment; however, the therapeutic effect relative to circRNA delivery is unclear. In the present investigation inflammatory factors, nerve injury, and cognitive function were assessed using a middle cerebral artery occlusion mouse model. The isolated exosomes were identified using transmission electron microscopy and further tested by leveraging exosome particles in a nanoparticle tracking approach. Differences in circRNA expression between exosomes and hypoxic pre-treated ADSC exosomes were analyzed by high-throughput sequencing. The phenotypic transformation of microglia was detected by immunofluorescence. The circRNA and downstream target were analyzed by bioinformatics, RT-qPCR, and luciferase report. Exosomes from hypoxic pre-treated ADSCs improved cognitive function by reducing neuronal damage in the hippocampus after cerebral infarction. Exosomes from hypoxic pre-treated ADSCs improved cognitive function via delivery of circ-Rps5. SIRT7 and miR-124-3p were circ-Rps5 downstream targets, which was confirmed by luciferase report analysis. miR-124-3p overexpression or SIRT7 downregulation reversed the circ-Rps5-mediated M2 microglial shift under LPS conditions. Circ-Rps5-modified ADSC exosome improved cognitive function by decreasing neuronal damage and shifting microglia from an M1 to M2 phenotype in the hippocampus. The study showed that exosomes from hypoxic pre-treated ADSCs attenuated acute ischemic stroke-induced brain injury via delivery of circ-Rps5 and promoted M2 microglia/macrophage polarization.

Yang H ，Tu Z ，Yang D ，Hu M ，Zhou L ，Li Q ，Yu B ，Hou S ... -  《-》

Exosomes from circRNA-Ptpn4 can modify ADSC treatment and repair nerve damage caused by cerebral infarction by shifting microglial M1/M2 polarization.

Adipose-derived stem cells (ADSCs) have been demonstrated to improve the microenvironment after a stroke. Increasing studies have confirmed that hypoxia pretreatment of ADSCs resulted in a better therapeutic effect, but the mechanism of treatment is unclear. We isolated ADSCs and exosomes. Then, constructed a middle cerebral artery occlusion (MCAO) mice model. High-throughput sequencing was used to identify the differential expression of circRNA. Immunofluorescence and ELISAs were used to detect the therapeutic effects of ADSC exosomes on MCAO. The luciferase reporter assay was used to detect the interaction relationships among circRNA-Ptpn4, miR-153-3p, and Nrf2. This study showed that exosomes from hypoxia pretreatment of ADSCs had significant effects in promoting functional recovery following in vivo MCAO, through suppressed inflammatory factor expression, and shifting the microglial from M1 to M2 polarization activation. The results showed that circRNA-Ptpn4 was highly expressed during hypoxia pretreatment of ADSCs exosomes. Exosomes from circ-Ptpn4-modified ADSCs had a greater ability to promote functional recovery. The circ-Ptpn4 delivered from ADSC exosomes induced microglia/macrophage polarization from M1 to M2 by suppressing miR-153-3p and enhancing Nrf2 expressions. Taken together, the results showed that exosomes from circRNA-Ptpn4 modified ADSC treatment repaired nerve damage caused by cerebral infarction by inducing microglial M1/M2 polarization.

Wang F ，Jiang M ，Chi Y ，Huang G ，Jin M ... -  《-》

Exosomes from ADSCs ameliorate nerve damage in the hippocampus caused by post traumatic brain injury via the delivery of circ-Scmh1 promoting microglial M2 polarization.

Traumatic brain injury (TBI) is an urgent global health issue. Neuroinflammation, due partially to microglia, can worsen or even cause neuropsychiatric disorders after a TBI. An increasing number of studies have found that adipose-derived stem cell (ADSC) derived exosomes can alleviate many diseases by delivering non-coding RNAs including circRNA and miRNAs, but the mechanism of action remains unclear. In the present investigation, we produced a TBI mouse model and isolated exosomes from their ADSCs before and after an hypoxic pretreatment. We then used next generation sequencing (NGS) to identify differentially expressed circRNAs and luciferase report assays to determine the relationship between the different noncoding RNAs (miRNA, circRNA and mRNA). The results show that we successfully isolated ADSCs which possessed a multidirectional differentiation potential. We then isolated exosomes from untreated ADSCs (Exos) and from hypoxia pretreated ADSCs (HExos). The HExos significantly decreased hippocampal nerve injury after TBI by decreasing M1 microglia mediated inflammatory cytokine expression and caused recovery of cognitive function. NGS data revealed that abnormal circ-Scmh1 expression plays a role in HExo mediated brain tissue preservation after TBI. Furthermore, luciferase report analysis found that miR-154-5p and STAT6 were the targets for circ-Scmh1. Interestingly, miR-154-5p overexpression or STAT6 inhibition reversed the circ-Scmh1 induced M2 microglial polarization. Overexpression of circ-Scmh1 increased the therapeutic effect of Exo on hippocampal nerve injury after TBI by promotion of M2 microglial polarization and decreased inflammatory induced hippocampal nerve injury. Taken together, we found that exosomes from ADSCs ameliorate nerve damage in the hippocampus post TBI through the delivery of circ-Scmh1 and the promotion of microglial M2 polarization.

Chen S ，Wang X ，Qian Z ，Wang M ，Zhang F ，Zeng T ，Li L ，Gao L ... -  《-》

Hypoxic pretreatment of adipose-derived stem cell exosomes improved cognition by delivery of circ-Epc1 and shifting microglial M1/M2 polarization in an Alzheimer's disease mice model.

Liu H ，Jin M ，Ji M ，Zhang W ，Liu A ，Wang T ... -  《Aging-US》

Hypoxic ADSC-derived exosomes enhance wound healing in diabetic mice via delivery of circ-Snhg11 and induction of M2-like macrophage polarization.

Diabetes mellitus is a major cause of blindness and chronic ulcers in the working age population worldwide. Former research have found that differentially expressed circular RNAs (circRNAs) are associated with hyperglycemia (HG)-induced endothelial cell damage. And adipose-derived stem cells (ADSCs)-exosome transplant have more therapeutic effect to enhance wound healing in diabetic mice by delivery circRNA. The current investigation employed high-throughput sequencing to identify circRNAs that are abnormally expressed in endothelial progenitor cells (EPCs) under HG conditions. The regulatory mechanism and predicted targets of one differentially expressed circRNA, circ-Snhg11, were investigated utilizing bioinformatics analyses, luciferase reporter assays, angiogenic differentiation assays, flow cytometric apoptosis analysis, and RT-qPCR. The result show that circ-Snhg11 expression decreased in EPCs under HG conditions and that overexpression of circ-Snhg11 suppressed HG-induced endothelial cell damage and M1-like macrophage polarization. miR-144-3p and HIF-1α were identified as downstream targets of circ-Snhg11, which was further verified by luciferase reporter analysis. miR-144-3p overexpression or HIF-1α inhibition reversed circ-Snhg11 protective effect on HG-induced endothelial cell dysfunction, as evidenced by increased apoptosis, abnormal vascular differentiation, and secretion of inflammatory factors. In addition, miR-144-3p overexpression or inhibition of HIF-1α reversed protective effect regarding circ-Snhg11 on M2-like macrophage polarization under HG conditions. These findings suggest that circ-Snhg11 promotes HIF-1α expression through miR-144-3p sponging. Our data demonstrate that circ-Snhg11 overexpression exosome from ADSCs suppresses HG-induced endothelial cell damage and induces M2-like macrophage polarization via the miR-144-3p/HIF-1α axis.

Shi R ，Jin Y ，Zhao S ，Yuan H ，Shi J ，Zhao H ... -  《-》