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Heat stroke (HS) is considered to be a severe systemic inflammatory reaction disease that is caused by high fever. The mortality of HS is high worldwide due to the lack of effective treatments. Presently, mesenchymal stem cells (MSCs) have been demonstrated to serve roles in inflammation and immune regulation. Therefore, the current study aimed to investigate the protective effect and mechanism of MSCs against the HS-induced inflammatory response and organ dysfunction. A rat model of HS was induced by a high-temperature environment and treated with MSCs via tail veins. The levels of molecular markers of organ function, inflammatory factors and chemokines were examined at days 1, 7, 14 and 28. Histological staining was performed on the intestines of rats and control groups, and the Chiu's scores of the two groups were compared. The results revealed that MSCs injection significantly reduced the mortality and inhibited the circulatory inflammatory response. Additionally, main organ function, such as in the liver and kidney, were significantly improved following MSCs infusion in HS rats. Furthermore, MSCs treatment significantly improved edema, necrosis and villus exfoliation of intestinal mucosa, and reduced the inflammatory response of intestinal tissue. These results indicated that MSC infusion had therapeutic effects on HS of rats by regulating the circulatory and intestinal inflammatory response. Moreover, MSCs may be able to protect organ function and promote tissue repair in HS. The results of the current study indicated that MSCs may be used as a potential method to treat HS and the resulting organ dysfunction.

Background Diabetic cardiomyopathy (DCM) is a cardiac complication of long-term uncontrolled diabetes and is characterized by myocardial fibrosis and abnormal cardiac function. Mesenchymal stem cells (MSCs) are multipotent cells with immunoregulatory and secretory functions in diabetes and heart diseases. However, very few studies have focused on the effect and the underlying mechanism of MSCs on myocardial fibrosis in DCM. Therefore, we aimed to explore the therapeutic potential of MSCs in myocardial fibrosis and its underlying mechanism in vivo and in vitro. Methods A DCM rat model was induced using a high-fat diet (HFD) combined with a low-dose streptozotocin (STZ) injection. After four infusions of MSCs, rat serum and heart tissues were collected, and the levels of blood glucose and lipid, cardiac structure, and function, and the degree of myocardial fibrosis including the expression levels of pro-fibrotic factor and collagen were analyzed using biochemical methods, echocardiography, histopathology, polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We infused prostaglandin E2 (PGE2)-deficient MSCs to DCM rats in vivo and established a system mimicking diabetic myocardial fibrosis in vitro by inducing cardiac fibroblasts with high glucose (HG) and coculturing them with MSCs or PGE2-deficient MSCs to further explore the underlying mechanism of amelioration of myocardial fibrosis by MSCs. Results Metabolic abnormalities, myocardial fibrosis, and cardiac dysfunction in DCM rats were significantly ameliorated after treatment with MSCs. Moreover, the levels of TGF-β, collagen I, collagen III, and collagen accumulation were markedly decreased after MSC infusion compared to those in DCM hearts. However, PGE2-deficient MSCs had decreased ability to alleviate cardiac fibrosis and dysfunction. In addition, in vitro study revealed that the concentration of PGE2 in the MSC group was enhanced, while the proliferation and collagen secretion of cardiac fibroblasts were reduced after MSC treatment. However, MSCs had little effect on alleviating fibrosis when the fibroblasts were pretreated with cyclooxygenase-2 (COX-2) inhibitors, which also inhibited PGE2 secretion. This phenomenon could be reversed by adding PGE2. Conclusions Our results indicated that MSC infusion could ameliorate cardiac fibrosis and dysfunction in DCM rats. The underlying mechanisms might involve the function of PGE2 secreted by MSCs.

Hyperoxia-induced lung injury (HILI) tends to develop bronchopulmonary dysplasia. Adipose-derived mesenchymal stem cell (ADMSC)-derived extracellular vesicles (EVs) hold great promise in alleviating lung injury. This study explored the mechanism of ADMSC-EVs in HILI. ADMSC-EVs were isolated and identified. The murine and cell models of HILI were established. HILI mice and cells were pre-treated with ADMSC-EVs. The lung dry/wet ratio, pathological structure, apoptosis, and inflammation of HILI mice were measured. The viability, apoptosis, and oxidative stress of HILI cells were measured. The internalization of EVs in lung and cells was observed by fluorescence labeling. The binding relationships between miR-21-5p and SKP2, and Nr2f2 and C/EBPα were analyzed. The binding of SKP2 and Nr2f2 and the Nr2f2 ubiquitination level were detected. ADMSC-EVs exerted preventive effects on HILI mice, evidenced by reduced lung dry/wet ratio, inflammation, and apoptosis in HILI mice. In vitro, EVs enhanced HILI cell viability and reduced apoptosis, inflammation, and oxidative stress. EVs carried miR-21-5p into lung cells to upregulate miR-21-5p expression and thereby target SKP2. SKP2 bound to Nr2f2 and promoted its ubiquitination degradation. EVs inhibited the binding of Nr2f2 and C/EBPα and further suppressed C/EBPα transcription. Collectively, ADMSC-EVs carrying miR-21-5p alleviated HILI via the SKP2/Nr2f2/C/EBPα axis. Role and mechanism of adipose-derived mesenchymal stem cell-derived extracellular vesicles in hyperoxia-induced lung injury. ADMSC-EVs upregulated miR-21-5p expression in cells by carrying miR-21-5p into lung cells, thereby promoting the binding of miR-21-5p and SKP2 mRNA, inhibiting the expression of SKP2, reducing the ubiquitination level of Nr2f2, increasing the expression of Nr2f2, promoting the binding of Nr2f2 and the C/EBPα promoter, upregulating C/EBPα mRNA level, and eventually alleviating HILI.

Background: Sepsis is the leading cause of death among patients, especially elderly patients, in intensive care units worldwide. However, there is no effective treatment for sepsis in the aging population. Therefore, we designed such a study to confirm the protective effect of MSCs against sepsis in the elderly and to explore its mechanisms.Methods: In this study, we established a sepsis model using naturally aged SD rats and injected 5×106 umbilical cord-derived MSCs via the tail vein. Each group of rats was analyzed for survival, examined for biochemical parameters, stained for organ histology, and analyzed for the Th cell subpopulation ratio and inflammatory cytokine levels by flow cytometry. Western blotting was performed to detect the activity of the JAK-STAT signaling pathway. We designed in vitro experiments to confirm the regulatory role of MSCs, and verified the possible mechanism using JAK/STAT inhibitors. Results: The results revealed that the 72 h survival rate of sepsis rats treated with MSCs was significantly increased, organ damage and inflammatory infiltration were reduced, the levels of organ damage indicators were decreased, the ratios of Th1/Th2 and Th17/Treg in peripheral blood and spleen were significantly decreased, the levels of pro-inflammatory cytokines such as IL-6 were decreased, the levels of anti-inflammatory cytokines such as IL-10 were increased, and the levels of STAT1 and STAT3 phosphorylation were reduced. These results were validated in in vitro experiments. Conclusions: Therefore, this study confirms that MSCs can control the inflammatory response induced by sepsis by regulating Th cells and inflammatory factors, and that this leads to reduction of tissue damage, protection of organ functions and ultimately improvement of survival in aged sepsis model rats. Inhibition of the JAK-STAT signaling pathway may be an important mechanism for their action.

Background Diabetic cardiomyopathy (DCM) is a common complication of diabetes and is characterized by chronic myocardial inflammation. Mesenchymal stem cell (MSC) infusions have recently been suggested to alleviate myocardial injury and ameliorate cardiac function. However, few studies have focused on the effects of MSCs in DCM. Therefore, we explored the effects of MSC-regulated macrophage polarization on myocardial repair in DCM. Methods A DCM rat model was induced by a high-fat diet and streptozotocin (STZ) administration and infused 4 times with MSCs. Rat blood and heart tissue were analyzed for blood glucose levels, lipid levels, echocardiography, histopathology, macrophage phenotype ratios and inflammatory cytokines, respectively. We mimicked chronic inflammation in vitro by inducing peritoneal macrophages with high glucose and LPS, then cocultured these macrophages with MSCs to explore the specific mechanism of MSCs on macrophage polarization. Results DCM rats exhibited abnormal blood glucose levels and lipid metabolism, cardiac inflammation and dysfunction. MSC infusion ameliorated metabolic abnormalities and preserved cardiac structure and function in DCM rats. Moreover, MSC infusion significantly increased the M2 phenotype macrophages and alleviated cardiac inflammation. Interestingly, this in vitro study revealed that the MSCs pretreated with a COX-2 inhibitor had little effect on M2 macrophage polarization, but this phenomenon could be reversed by adding prostaglandin E2 (PGE2). Conclusions Our results suggested that MSC infusions can protect against cardiac injury in DCM rats. The underlying mechanisms may include MSC-enhanced M2 macrophage polarization via the COX-2-PGE2 pathway.

Background: Sepsis is the leading cause of death among ICU patients, especially elderly patients. We designed this study to confirm the protective effect of MSCs against sepsis in aged rats. Methods: We used naturally aged SD rats to establish sepsis model and injected 5×106 umbilical cord-derived MSCs via the tail vein. Each group of rats was analyzed for survival, examined for biochemical parameters, stained for organ histology, and analyzed for the Th cell subpopulation ratio and inflammatory cytokine levels by flow cytometry. Western blotting was performed to detect the activity of the JAK-STAT signaling pathway. Vitro experiments were designed to confirm the effect of MSCs, and verified the possible mechanism using JAK/STAT inhibitors. Findings: The 72 h survival rate of sepsis rats treated with MSCs was significantly increased, organ damage and inflammatory infiltration were reduced, the levels of organ damage indicators were decreased, the ratios of Th1/Th2 and Th17/Treg in peripheral blood and spleen were significantly decreased, the levels of pro-inflammatory cytokines were decreased, the levels of anti-inflammatory cytokines were increased, and the levels of STAT1 and STAT3 phosphorylation were reduced. These results were validated in in vitro experiments. Interpretation: This study confirms that MSCs can control the inflammatory response induced by sepsis by regulating Th cells and inflammatory factors, and that this leads to reduction of tissue damage, protection of organ functions and ultimately improvement of survival in aged sepsis model rats. Inhibition of the JAK-STAT signaling pathway may be an important mechanism for their action. Funding Information: Not applicable. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was approved by the Ethics Committee of the Chinese PLA General Hospital. Animal experiments were approved by the Experimental Animal Welfare Ethics Committee of Chinese PLA General Hospital. Umbilical cords were obtained from the Department of Obstetrics and Gynecology, the First Medical Center, Chinese PLA General Hospital, China, and the mothers signed an informed consent.

Background Hyperoxia-induced lung injury (HILI) is an acute lung injury (LI) induced by extended periods of exposure to hyperoxia. Alleviating LI by bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) and microRNAs (miRs) has been previously reported. This study is devised to probe the interaction between BMSCs-Exos and miR-425 in HILI. Methods Firstly, BMSCs-Exos were isolated and identified. Then, HILI rat models and RLE-6TN cell models were successfully established and treated by BMSCs-Exos. Afterwards, functional assays were conducted to explore cell biological behaviors in models, with miR-425 expression detected. Then, the target relation between miR-425 and PTEN was clarified by luciferase reporter assay. Eventually, expression of PTEN and the PI3K/Akt axis was assessed by Western blotting and qRT-PCR. Results BMSCs-Exos promoted miR-425 expression and attenuated HILI and H2O2 induced RLE-6TN cell injury as evidence by alleviated lung cell injury, decreased TUNEL-positive cells, induced cell viability and declined apoptosis (all p Conclusion Our data supported that miR-425 in BMSCs-Exos inhibits HILI by targeting PTEN and upregulating the PI3K/AKT axis. This study may provide personalized interventions for HILI remedy.

Background: Heat stroke (HS) is a severe systemic inflammatory response disease caused by high fever, mainly with nervous system damage. Currently, mesenchymal stem cells (MSCs) have inflammation and immunomodulatory effects. Therefore, we aimed to explore the protective effect and mechanism of MSCs on HS-induced excessive inflammation and neurological dysfunction.Methods: A heat stroke Sprague-Dawley (SD) rat model was established at continuous high temperature (42 °C) and high humidity (70%-80%). After modeling, the rats were randomly divided into a heat stroke model group (HS group), a MSCs treatment group (HS+MSCs group), and a Control group in which the rats were kept at room temperature without any treatment. Survival analysis, neurological deficit scoring, pathological staining of hippocampus and cerebellum, immunofluorescence staining of microglia cells, and tissue level detection of inflammatory cytokines were performed in the three groups on day 1, 3, 7, 14 and 28 separately.Results: After heat stroke modeling, the rats were severely paralyzed and had a high mortality. MSCs treatment significantly reduced the mortality in both early stage (day 3) and late stage (day 28). MSCs treatment also significantly reduced the neurological impairment of heat stroke rats, and improved hippocampal and cerebellar pathology and neuronal cell damage. In addition, MSCs treatment significantly inhibited the overactivation of microglia in the hippocampus of HS rats as well as the levels of pro-inflammatory factors and chemokines in the hippocampus. In the early stage (day 1) of MSCs treatment, the activation of cerebellar microglia in the heat stroke rats was significantly promoted. Meanwhile, MSCs treatment had no significant inhibitory effect on the levels of pro-inflammatory factors in the cerebellar tissues of heat stroke rats, but can inhibit the levels of chemokines in the early stage.Conclusions: The application of MSCs for heat stroke treatment in rats can significantly reduce the mortality and neurological defects and improve the hippocampal injury. Meanwhile, MSCs can inhibit the over-activation of microglia cells in the hippocampus of heat stroke rats, which may be a mechanism of MSCs in protecting heat-stroke-caused hippocampal injury.

Heat stroke (HS) is the most acute type of heat illness accompanied with serious central nervous system (CNS) dysfunction. Despite the pathological process being clearly studied, effective treatment is deficient. Currently, mesenchymal stem cells (MSCs) have been demonstrated to have neuroprotective effects as there are no old ones. Thus, the purpose of the present study was to explore the neuroprotective effects and mechanisms of MSCs against HS-induced CNS injury. HS in rat models was induced by a high-temperature environment and treated with MSCs via the tail vein. The results demonstrated that MSC injection significantly reduced the mortality and inhibited the circulation inflammatory response. Moreover, the HS-induced neurological deficit and neuronic damage of the hippocampus were significantly ameliorated by MSC administration. In addition, MSC administration significantly restored astrocytes and inhibited cerebral inflammatory response. These results indicate that MSC infusion has therapeutic effects in HS of rats by regulating the circulation and cerebral inflammatory response. Moreover, astrocytes increased in MSC-treated HS rats when compared with the untreated ones. This may suggest a potential mechanism for HS prevention and therapy through MSC administration.

OBJECTIVE: This study aimed to explore the functions and possible underlying regulatory molecules and mechanisms of monocytes and macrophages under early atherosclerotic conditions. METHODS: THP-1-derived monocytes or macrophages were induced by 50 μg/ml oxidized low density lipoprotein (ox-LDL) for 24 hours, and the degree of lipid metabolism and inflammation were determined. In addition, we identified differentially expressed genes, noncoding ribonucleic acids (RNAs), pathways and mechanisms by RNA sequencing, and performed further correlation analysis and molecular expression verification. RESULTS: Monocytes could not form foam cells with oil red O staining directly and had low levels of lipids as determined by total cholesterol and triglycerides assays, cholesterol uptake molecules CD36, the class A macrophage scavenger receptor and lectin-like oxidized low-density lipoprotein receptor-1 and cholesterol efflux molecules ATP binding cassette transporter A1, ATP binding cassette transporter G1 and liver X receptor α, and inflammatory factors, which were markedly different from those in macrophages. Additionally, sequencing data showed obviously differentially expressed genes, microRNAs and long noncoding RNAs in the atherosclerotic group. We identified 15 upregulated and downregulated genes, and 10 biological processes and pathways involved in atherosclerosis. Specifically, fatty acid desaturase 2 and apolipoprotein A1 in the peroxisome proliferator-activated receptor signaling pathway were differentially expressed in stimulated macrophages, whereas no changes were observed in the monocyte groups. Furthermore, correlation analysis showed differential expressed lncRNAs targeting miRNAs and mRNAs, and 24 competing endogenous RNA (ceRNA) networks of long noncoding RNA-microRNA-messenger RNA in early oxidative macrophages. CONCLUSIONS: Monocytes did not directly participate in lipid metabolism before differentiation into macrophages at the early stage in vitro. Furthermore, noncoding RNAs and ceRNA networks might play important roles in regulating the lipid metabolism of macrophages at the early stage of atherosclerosis.

It is widely accepted that infusion of mesenchymal stem cells (MSCs) ameliorates hyperglycemia by alleviating insulin resistance in rats with type 2 diabetes mellitus (T2D). However, the detailed underlying mechanisms are not clearly defined. Mitsugumin 53 (MG53) is an E3 ligase that has recently been implicated in the aggravation of insulin resistance by promoting the ubiquitinoylation of insulin receptor substrate‑1 (IRS‑1) in skeletal muscles. It was therefore hypothesized that MG53 may be involved in MSC‑mediated therapeutic effects on insulin resistance. To test this hypothesis, in the present study, T2D rat models were induced by a high‑fat diet combined with streptozotocin administration and MSC infusion was performed four times (once every 2 weeks for 8 weeks). The therapeutic effects of MSC infusion on insulin resistance were evaluated and the effect on the expression of MG53 and insulin receptor signaling elements in skeletal muscle was also investigated by immunofluorescence staining and western blotting. The results demonstrated that MSC infusion ameliorated hyperglycemia and insulin resistance in T2D rats. Furthermore, MSC infusion inhibited MG53 elevation and reversed the decreases in glucose transporter type 4, insulin receptor, IRS‑1 and phosphorylated‑AKT levels in the skeletal muscle of T2D rats. These results indicated that MSC infusion has therapeutic effects in rats and that MG53 in skeletal muscle may be a promising novel therapeutic target protein for MSC‑mediated amelioration of insulin resistance in T2D.

Considering that the spleen plays an important role in the occurrence and development of diabetes, we aimed at investigating the role of the spleen in the treatment of type 2 diabetes (T2D) with adipose tissue-derived stem cells (ADSCs). We established a T2D/splenectomy (SPX) rat model by using high-fat diet/streptozotocin administration with SPX, assessed the therapeutic effects of ADSCs, and explored the possible mechanism. A single ADSC infusion was found to ameliorate hyperglycemia and insulin resistance in diabetic rats, accompanied by a considerable number of ADSCs homing to the spleens in T2D rats. Moreover, four times of infusion of ADSCs resulted in a more significant reduction of blood glucose and insulin resistance, whereas SPX exacerbated hyperglycemia and insulin resistance and attenuated the effects of ADSCs. In addition, ADSC infusion promoted anti-inflammatory cytokine interleukin (IL)-10 expression and inhibited pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor (TNF)-α expression in both the spleen and serum of T2D rats without SPX. ADSCs also inhibited serum IL-6, IL-1β, and TNF-α expression, but cannot promote IL-10 expression in T2D rats with SPX. Therefore, these data indicate that the effect of ADSCs ameliorating hyperglycemia and insulin resistance may be partially through promoting spleen-derived anti-inflammatory cytokine IL-10 expression. These novel findings further confirmed the essential role of the spleen in the ADSC treatment of T2D and provide an important theoretical basis for the potential application of ADSCs in T2D therapy.