Administration of exosomes derived from mesenchymal stromal cells (MSCs) could improve some neurologic conditions by transferring functional biomolecules to recipient cells. Furthermore, exosomes from hypoxic progenitor cells exerted better therapeutic effects in organ injury through specific cargoes. However, there are no related reports about whether exosomes derived from MSCs or hypoxia-preconditioned MSCs (PC-MSCs) could prevent memory deficits in Alzheimer disease (AD). In this study, the exosomes derived from MSCs or PC-MSCs were systemically administered to transgenic APP/PS1 mice. The expression of miR-21 in MSCs was significantly increased after hypoxic treatment. Injection of exosomes from normoxic MSCs could rescue cognition and memory impairment according to results of the Morris water maze test, reduced plaque deposition, and Aβ levels in the brain; could decrease the activation of astrocytes and microglia; could down-regulate proinflammatory cytokines (TNF-α and IL-1β); and could up-regulate anti-inflammatory cytokines (IL-4 and -10) in AD mice, as well as reduce the activation of signal transducer and activator of transcription 3 (STAT3) and NF-κB. Compared to the group administered exosomes from normoxic MSCs, in the group administered exosomes from PC-MSCs, learning and memory capabilities were significantly improved; the plaque deposition and Aβ levels were lower, and expression of growth-associated protein 43, synapsin 1, and IL-10 was increased; and the levels of glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, TNF-α, IL-1β, and activation of STAT3 and NF-κB were sharply decreased. More importantly, exosomes from PC-MSCs effectively increased the level of miR-21 in the brain of AD mice. Additionally, replenishment of miR-21 restored the cognitive deficits in APP/PS1 mice and prevented pathologic features. Taken together, these findings suggest that exosomes from PC-MSCs could improve the learning and memory capabilities of APP/PS1 mice, and that the underlying mechanism may lie in the restoration of synaptic dysfunction and regulation of inflammatory responses through regulation of miR-21.-Cui, G.-H., Wu, J., Mou, F.-F., Xie, W.-H., Wang, F.-B., Wang, Q.-L., Fang, J., Xu, Y.-W., Dong, Y.-R., Liu, J.-R., Guo, H.-D. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice.

Cardiovascular disease has been established as a major cause of morbidity and mortality worldwide, resulting in a huge burden to patients, families, and society. Traditional Chinese Medicine (TCM) presents several advantages for the prevention and treatment of cardiovascular diseases including multitargets, multi-ingredients, fewer side effects, and low cost. In this study, a rat model of myocardial infarction (MI) was established by ligating the anterior descending branch of the left coronary artery, and the effect of the Taohong Siwu decoction (THSWD) on cardiac function was evaluated in MI rats. Following the intragastric administration of THSWD, the cardiac function was examined using echocardiography. The infarct size and collagen deposition in the infarct area were measured using Masson's trichrome staining, and the number of CD31- and α-SMA-positive blood vessels in the peri-infarct and infarct area was evaluated by immunofluorescent staining. The mRNA expression of bFGF, IGF-1, and HGF was detected using RT-PCR assay. Cell apoptosis in the infarcted area was assessed by TUNEL staining, and the p-Akt level was detected using the western blot assay. The mitochondrial ROS production was measured using MitoSOX staining, and mitochondrial dynamics and mitophagy were evaluated with western blotting 7 days after THSWD treatment. THSWD increased the ejection fraction (EF) and fractional shortening (FS) values in the rat hearts; however, no statistical difference was found between the THSWD and MI groups 4 weeks after treatment. Furthermore, THSWD significantly decreased the value of the left ventricular end-systolic volume (LVESV). Compared with the model group, THSWD significantly increased the expression of IGF-1 and bFGF, reduced collagen deposition, promoted angiogenesis, reduced cell apoptosis, and activated the PI3K/Akt signaling pathway. Notably, THSWD significantly decreased mitochondrial ROS production and Fis1 expression. No statistical differences were observed in the expression of mitochondrial LC3B and Mfn1 between the THSWD and control groups. In summary, THSWD may possess a beneficial effect on cardiac function by improving the local ischemic microenvironment and by decreasing mitochondrial fission after MI. Hence, this may present a promising auxiliary strategy in the treatment of ischemic cardiomyopathy such as MI.

The lower cell survival and retention in the hostile microenvironment after transplantation has been implicated as a major bottleneck in the advancement of stem cell therapy for myocardial infarction (MI). In this study, we designed a novel self‐assembling peptide (SAP) by attaching prosurvival peptide QHREDGS derived from angiopoeitin‐1 to the known SAP, RADA16‐I. The mesenchymal stem cells (MSCs) were harvested from male rats and cytoprotective effect of this designer SAP (DSAP) on cultured MSCs was detected by Hoechst 33342 staining after being exposed to oxygen and glucose deprivation (OGD). The cytoprotective effect of MSCs seeded in DSAP (DSAP‐MSCs) on OGD treated cardiomyocytes was examined by TUNEL staining, phosphorylated (p‐) protein kinase B (Akt) level, and ELISA. The therapeutic potential of MSC transplantation carried in DSAP was evaluated in a female rat MI model. PBS, MSCs alone, MSCs seeded in SAP (SAP‐MSCs), or DSAP‐MSCs were transplanted into the border of the infarcted area, respectively. DSAP not only increased the proliferation of MSCs and decreased apoptosis of MSCs after OGD treatment but also promoted the secretion of IGF‐1 and HGF in MSCs. Treatment with culture supernatant of DSAP‐MSCs markedly reduced the percentage of apoptotic cardiomyocytes and increased the level of p‐Akt. Compared with the MSC group and SAP‐MSC group, DSAP‐MSC injection improved cardiac function and reduced infarct size, collagen content, and cell apoptosis. The number of Y chromosome–positive cells and microvessels in the DSAP‐MSC group was higher than those in the MSC group and SAP‐MSC group. Moreover, DSAP‐MSC transplantation down‐regulated the expression of IL‐6 and IL‐1β and up‐regulated the level of VEGF and HGF. Interestingly, miR‐21 was enriched in DSAP‐MSC‐derived exosomes (DSAP‐MSC‐Exos) and the protection against cardiomyocyte apoptosis by DSAP‐MSC‐Exos was inhibited when miR‐21 was knocked down. Furthermore, miR‐21 contributed to the improvement of cardiac function after DSAP‐MSC‐Exo injection in a rat model of MI. Additionally, the combination of DSAP and cardiotrophin‐1 (Ctf1) pretreatment further improved the survival of MSCs and the efficiency of MSC transplantation. We proposed QHREDGS‐modified SAP as an effective cell delivery system and demonstrated that MSC transplantation in this DSAP promoted angiogenesis and paracrine, thereby reducing scar size and cell apoptosis as well as improving cardiac function probably via exosome‐mediated miR‐21 after MI. Furthermore, for the first time, we proposed that DSAP, especially working together with Ctf1 pretreatment, could be a valuable way to improve the survival of MSCs and the efficiency of MSC transplantation after MI.—Cai, H., Wu, F.‐Y., Wang, Q.‐L., Xu, P., Mou, F.‐F., Shao, S.‐J., Luo, Z.‐R., Zhu, J., Xuan, S.‐S., Lu, R., Guo, H.‐D. Self‐assembling peptide modified with QHREDGS as a novel delivery system for mesenchymal stem cell transplantation after myocardial infarction. FASEB J. 33, 8306–8320 (2019). http://www.fasebj.org

No abstract

EA reduces neuronal apoptosis, enhances degradation of Aβ, and improves learning/memory in AD rats by upregulating the autophagy pathway.