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 ... -  《-》

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 Hypoxic Pretreatment ADSCs Ameliorate Cardiac Damage Post-MI via Activated circ-Stt3b/miR-15a-5p/GPX4 Signaling and Decreased Ferroptosis.

Accumulation studies confirmed that oxidative stress caused by ischemia after myocardial infarction (MI) is an important cause of ventricular remodeling. Exosome secretion through hypoxic pretreatment adipose-derived mesenchymal stem cells (ADSCs) ameliorates myocardial damaging post-MI. However, if ADSCs exosome can improve the microenvironment and ameliorate cardiac damage post-MI still unknown. Next-generation sequencing (NGS) was used to study abnormally expressed circRNAs in hypoxic pretreatment ADSC exosomes (HExos) and untreated ADSC exosomes (Exos). Bioinformatics and luciferase reporting were used to elucidate interaction correlation related to circRNA, mRNA, and miRNA. HL-1 cells were used to analyze the reactive oxygen species (ROS) and apoptosis under hypoxic conditions using immunofluorescence and flow cytometry. An MI mouse model was constructed and the therapeutic effect of Exos was determined using immunohistochemistry, immunofluorescence, and ELISA. The results showed that HExos had a more pronounced treatment effect than ADSC Exos on cardiac damage amelioration after MI. NGS showed that circ-Stt3b plays a role in HExo-mediated cardiac damage repair after MI. Overexpression of circ-Stt3b decreased apoptosis, ROS level, and inflammatory factor expression in HL-1 cells under hypoxic conditions. Bioinformatics and luciferase reporting data validated miR-15a-5p and GPX4 as downstream circ-Stt3b targets. GPX4 downregulation or miR-15a-5p overexpression reversed protective effect regarding circ-Stt3b upon HL-1 cells after exposure to a hypoxic microenvironment. Overexpression of circ-Stt3b increased the treatment effect of ASDSC Exos on cardiac damage amelioration after MI. Taken together, the study results demonstrated that Exos from hypoxic pretreatment ADSCs ameliorate cardiac damage post-MI through circ-Stt3b/miR-15a-5p/GPX4 signaling activation and decreased ferroptosis.

Liu J ，Wang Z ，Lin A ，Zhang N ... -  《-》

Exosomes from hypoxic ADSCs ameliorate neuronal damage post spinal cord injury through circ-Wdfy3 delivery and inhibition of ferroptosis.

Exosomes generated from adipose-derived mesenchymal stem cells (Exos), and in particular hypoxia-pretreated ADSCs (HExos), possess therapeutic properties that promote spinal cord repair following spinal cord injury (SCI). Nevertheless, the regulatory mechanisms through which HExos exert their effects remain unclear. Here, next-generation sequencing (NGS) was utilized to examine abnormal circRNA expression comparing HExos to Exos. Bioinformatics analysis and RNA pulldown assays together with luciferase reporter assays were applied to determine interactions among miRNAs, mRNAs and circRNAs. ELISA and immunofluorescence staining were used to examine inflammatory cytokine levels, apoptosis and ROS deposition in LPS-treated HT-22 cells, respectively. The therapeutic effects of Exos and HExos on a mouse model of SCI were analyzed by immunohistochemistry and immunofluorescence staining. Our findings confirmed that HExos have more significant therapeutic influences on decreasing ROS and inflammatory cytokine levels post-SCI than Exos. NGS revealed that circ-Wdfy3 expression levels were significantly higher in HExos than Exos. Downregulation of circ-Wdfy3 led to a decrease in HExo-induced therapeutic effects on spinal cord repair post-SCI, indicating that circ-Wdfy3 has a critical role in the regulation of HExo-mediated protection against SCI. Our bioinformatics, RNA pulldown and luciferase reporter data demonstrated that GPX4 and miR-423-3p were downstream targets of circ-Wdfy3. GPX4 downregulation or miR-423-3p overexpression reversed the protective effects of circ-Wdfy3 on LPS-treated HT-22 cells. Furthermore, overexpression of circ-Wdfy3 led to an in increase in the Exo-induced therapeutic effects on spinal cord repair post-SCI through the inhibition of ferroptosis. circ-WDfy3-overexpressing Exos promote spinal cord repair post-SCI through mediation of ferroptosis via the miR-138-5p/GPX4 pathway.

Shao M ，Ye S ，Chen Y ，Yu C ，Zhu W ... -  《-》

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 ... -  《-》