Background: Small intestinal ischemia-reperfusion (IR) injury is a common intestinal disease with high morbidity and mortality. Mesenchymal stem cells (MSCs) have been increasingly used in various intestinal diseases. This study aimed to evaluate the therapeutic effect of hair follicle MSCs (HFMSCs) on small intestinal IR injury.Methods: We divided Sprague–Dawley rats into three groups: the sham group, IR group and IR + HFMSCs group. A small intestinal IR injury rat model was established by clamping of the superior mesenteric artery (SMA) for 30 min and reperfusion for 2 h. HFMSCs were cultured in vitro and injected into the rats through the tail vein. Seven days after treatment, the intrinsic homing and differentiation characteristics of the HFMSCs were observed by immunofluorescence and immunohistochemical staining, and the paracrine mechanism of HFMSCs was assessed by Western blotting and enzyme-linked immunosorbent assay (ELISA).Results: A small intestinal IR injury model was successfully established. HFMSCs could home to damaged sites, express proliferating cell nuclear antigen (PCNA) and intestinal stem cell (ISC) markers, and promote small intestinal ISC marker expression. The expression levels of angiopoietin-1 (ANG1), vascular endothelial growth factor (VEGF) and insulin growth factor-1 (IGF1) in the IR + HFMSCs group were higher than those in the IR group. HFMSCs could prevent IR-induced apoptosis by increasing B-cell lymphoma-2 (Bcl-2) expression and decreasing Bcl-2 homologous antagonist/killer (Bax) expression. Oxidative stress level detection showed that the malondialdehyde (MDA) content was decreased, while the superoxide dismutase (SOD) content was increased in the IR + HFMSCs group compared to the IR group. An elevated diamine oxidase (DAO) level reflected the potential protective effect of HFMSCs on the intestinal mucosal barrier.Conclusion: HFMSCs are beneficial to alleviate small intestinal IR injury through intrinsic homing to the small intestine and by differentiating into ISCs, via a paracrine mechanism to promote angiogenesis, reduce apoptosis, regulate the oxidative stress response, and protect intestinal mucosal function potentially. Therefore, this study suggests that HFMSCs serve as a new option for the treatment of small intestinal IR injury.
BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. Non-coding RNAs play an important role in HCC. This study aims to identify a senescence-related non-coding RNA network-based prognostic model for individualized therapies for HCC.MethodsHCC subtypes with senescence status were identified on the basis of the senescence-related genes. Immune status of the subtypes was analyzed by CIBERSORT and ESTIMATE algorithm. The differentially expressed mRNAs, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) were identified between the two HCC subtypes. A senescence-based competing endogenous RNA (ceRNA) co-expression network in HCC was constructed. On the basis of the ceRNA network, Lasso Cox regression was used to construct the senescence-related prognostic model (S score). The prognosis potential of the S score was evaluated in the training dataset and four external validation datasets. Finally, the potential of the prognostic model in predicting immune features and response to immunotherapy was evaluated.ResultsThe HCC samples were classified into senescence active and inactivate subtypes. The senescence active group showed an immune suppressive microenvironment compared to the senescence inactive group. A total of 2,902 mRNAs, 19 miRNAs, and 308 lncRNAs were identified between the two subtypes. A ceRNA network was constructed using these differentially expressed genes. On the basis of the ceRNA network, S score was constructed to predict the prognosis of patients with HCC. The S score was correlated with immune features and can predict response to immunotherapy of cancer.ConclusionThe present study analyzed the biological heterogeneity across senescence-related subtypes and constructed a senescence-related ceRNA-network-based prognostic model for predicting prognosis and immunotherapy responsiveness.
Liver cirrhosis (LC) involves multiple systems throughout the body, and patients with LC often die of multiple organ failure. However, few drugs are useful to treat LC. Hair follicle mesenchymal stem cells (HF-MSCs) are derived from the dermal papilla and the bulge area of hair follicles and are pluripotent stem cells in the mesoderm with broad prospects in regenerative medicine. As an emerging seed cell type widely used in skin wound healing and plastic surgery, HF-MSCs show considerable prospects in the treatment of LC due to their proliferation and multidirectional differentiation capabilities. We established an LC model in C57BL/6J mice by administering carbon tetrachloride (CCl4) and injected HF-MSCs through the tail vein to explore the therapeutic effects and potential mechanisms of HF-MSCs on LC. Here, we found that HF-MSCs improved liver function and ameliorated the liver pathology of LC. Notably, PKH67-labeled HF-MSCs were detected in the injured liver and expressed the hepatocyte-specific markers cytokeratin 18 (CK18) and albumin (ALB). In addition, in contrast to that in the LC group, the α-SMA expression showed a decreasing trend in the treatment group in vitro and in vivo, indicating that the pathological activation of hepatic stellate cells (HSCs) was inhibited by HF-MSC treatment. Moreover, the levels of transforming growth factor β (TGF-β1) and p-Smad3, a signaling molecule downstream of TGF-β1, were increased in mice with LC, while HF-MSC treatment reversed these changes in vivo and in vitro. Based on these findings, HF-MSCs may reverse LC by blocking the TGF-β/Smad pathway and inhibiting the pathological activation of HSCs, which may provide evidence for the application of HF-MSCs to treat LC.
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