BACKGROUND: Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood.
METHODS: hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-β1 in exosomes were evaluated by Western blot.
RESULTS: Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-β1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-β1 in exosomes, and the results showed that exosomes had high expression of TGF-β1.
CONCLUSIONS: By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-β1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TβR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.

Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions requires repeated intravitreal injections, which may lead to complications such as infection and hemorrhage. So, we have developed a noninvasive method for treating CNV with nanoparticles, namely, Angiopoietin1-anti CD105-PLGA nanoparticles (AAP NPs), which targets the CNV to enhance drug accumulation at the site. These nanoparticles, with PLGA as a carrier, can slowly release encapsulated Angiopoietin 1 (Ang 1) and target the choroidal neovascularization marker CD105 to enhance drug accumulation, increases vascular endothelial cadherin (VE-cadherin) expression between vascular endothelial cells, effectively reduce neovascularization leakage and inhibit Angiopoietin 2(Ang 2) secretion by endothelial cells. In a rat model of laser-induced CNV, intravenous injection of AAP NPs exerted a good therapeutic effect in reducing CNV leakage and area. In short, these synthetic AAP NPs provide an effective alternative treatment for AMD and meet the urgent need for noninvasive treatment in neovascular ophthalmopathy. STATEMENT OF SIGNIFICANCE: This work describes the synthesis, injection-mediated delivery, in vitro and in vivo efficacy of targeted nanoparticles with encapsulated Ang1; via these nanoparticles, the drug can be targeted to choroidal neovascularization lesions for continuous treatment. The release of Ang1 can effectively reduce neovascularization leakage, maintain vascular stability, and inhibit Ang2 secretion and inflammation. This study provides a new approach for the treatment of wet age-related macular degeneration.

The modeling of chimeric antigen receptor (CAR) T cell therapies has been mostly focused on immunodeficient models. However, there are many advantages in studying CAR-T cell biology in an immunocompetent setting. We generated a fully murine CAR targeting CD105 (endoglin), a component of the TGFβ receptor expressed on the surface of certain solid tumors and acute leukemias. CD105-targeted CAR-T cells can be grown from various murine backgrounds, tracked in vivo by congenic marks, and be activated by CD105 in isolation or expressed by tumor cells. CD105-targeted CAR-T cells were toxic at higher doses but proved safe in lower doses and modestly effective in treating wild-type B16 melanoma-bearing mice. CAR-T cells infiltrating the tumor expressed high levels of exhaustion markers and exhibited metabolic insufficiencies. We also generated a human CD105 CAR, which was efficacious in treating human melanoma and acute myeloid leukemia in vivo. Our work details a new murine model of CAR-T cell therapy that can be used from immunologists to further our understanding of CAR-T cell biology. We also set the foundation for further exploration of CD105 as a possible human CAR-T cell target.

Blood vessel passage on CT exerts a vital part in early diagnosis as well as treatment of carcinoma of the lungs. Intratumoral microvascular density (iMVD) has gradually become the focus of research on biological behavior, appearance, and evolution of malignant tumors nowadays. The aim of this paper was to verify whether there is a correlation between the iMVD and the vascular morphology of ground glass nodules (GGNs). A total of 109 patients with pulmonary GGN were classified into three groups (I,II, and III) according to the vascular morphology on CT, and their expression of CD31-, CD34-, and CD105-labeled iMVD was detected by the streptoavidin-biotin method, statistically analyzing the iMVD values of each group. The expression of CD31, CD34, and CD105 in different lung tissues was significantly different, with remarkably higher iMVD in lung cancer tissues than in adjacent normal lung tissues. In the imaging sort of types I, II, and III according to the means of vascular passage, the iMVD expression of CD31, CD34, and CD105 was significantly different between groups. These data suggest that the presence and the abnormal morphology of vessels seen within GGNs indicate the occurrence and progression of lung cancer in pathology. It offers a strong theoretical foundation for early diagnosis of carcinoma of the lungs, thus providing a more precise clinical diagnosis and prognosis of early-stage lung cancer.

UNASSIGNED: As the treatment target, the imaging information and histologic characteristics of the thrombus may differ according to the stroke subtype. This study aimed to provide the correlative study of stroke etiology with the non-contrast CT, and histological composition of retrieved clots in acute ischemic stroke (AIS).
UNASSIGNED: A total of 94 patients with AIS who underwent the endovascular treatment with successfully retrieved clots from January 2017 to October 2020 were enrolled in the present study. Histological analysis was performed using hematoxylin and eosin (H&E) staining and immunostaining with CD3, CD20, CD105, and actin antibodies. CT obtained at the patients\' admission was to measure the attenuation and volume of all thrombus.
UNASSIGNED: A total of 94 subjects were included in this study. Fifty-six patients were classified as cardioembolic (CE), and 38 were classified with large-artery atherosclerosis (LAA). The subjects with LAA tend to exhibit higher actin and CD105 levels, and lower Hounsfield Unit (HU) values than subjects with CE. After adjusting for confounders, the actin was positively correlated with CD105 but not with HU values. Logistics regression shows actin was valuable for the prediction of LAA (OR, 1.148; 95% CI, 1.075-1.227; p < 0.001), even adjusted for age, sex, and intervention type (OR, 1.129; 95% CI, 1.048-1.216; p = 0.001), CT density and CD105 (OR, 1.161; 95% CI, 1.056-1.277; p = 0.002). Actin levels have a strong accuracy in differentiating LAA from CE, especially combined with CT density and CD105, which yielded a sensitivity of 63.2%, a specificity of 89.3%, with the area under the curve (AUC) at 0.821 (95% CI, 0.731-0.912).
UNASSIGNED: Our findings suggest that actin\'s level was a major factor differentiating atherothrombotic origin strokes from the cardioembolic stroke.
UNASSIGNED: ChiCTR2100051173.

Cancer is one of the diseases with the highest morbidity and mortality rates worldwide, and its therapeutic options are inadequate. The endothelial glycoprotein, also known as CD105, is a type I transmembrane glycoprotein located on the surface of the cell membranes and it is one of the transforming growth factor-β (TGF-β) receptor complexes. It regulates the responses associated with binding to transforming growth factor β1 egg (Activin-A), bone morphogenetic protein 2 (BMP-2), and bone morphogenetic protein 7 (BMP-7). Additionally, it is involved in the regulation of angiogenesis. This glycoprotein is indispensable in the treatment of tumor angiogenesis, and it also plays a leading role in tumor angiogenesis therapy. Therefore, CD105 is considered to be a novel therapeutic target. In this study, we explored the significance of CD105 in the diagnosis, treatment and prognosis of various tumors, and provided evidence for the effect and mechanism of CD105 on tumors.

This study investigates the association of CD105 (endoglin) with the invasiveness of paclitaxel-resistant ovarian cancer (OC) cells and explores the potential mechanism. A paclitaxel-resistant OC cell line OC3/TAX300, which expresses the stem cell marker CD105 and has a high invasive potential, was established in our previous study. After CD105 knockdown using CD105 siRNA, the invasiveness of the OC cells was decreased, and the chemo-resistance was reversed, but the CD105 overexpression was related to the poor survival of the primary OC patients. The differentially expressed genes were investigated in the OC cells after the CD105 knockdown. The results showed that, in the CD105-siRNA transfected cells, the expressions of some genes (such as KIAA0125, SSTR5-AS1, CDH18, MIAT, NDRG1, E-cadherin, DUSP1, MAL, MYC, and JAK3) were significantly upregulated, but the expressions of other genes (such as PRKAR2B, KLK10, DDX17, and lncRNA SNHG7) were markedly downregulated. Several genes, such as NDRG1 and E-cadherin, are known to be related to cancer metastasis and the epithelial-mesenchymal transition (EMT). A KEGG analysis found that 264 signaling pathways changed after the CD105 knockdown, of which 27 signaling pathways showed significant enrichment. Our results show that CD105 is related to the metastasis of OC and may promote the EMT of OC by inhibiting NDRG1 and E-cadherin. MYC, JAK3, and IKBKB mediate the CD105-induced metastasis of OC via the MAPK/PI3K/AKT and JAK/STAT signaling pathways in the OC cells. Therefore, inhibiting the CD105 expression may be useful for treating OC.

Objective: Bevacizumab is a recombinant humanized monoclonal antibody that blocks vascular endothelial growth factor (VEGF) with clear clinical benefits. However, overall survival of some cancer types remains low owing to resistance to bevacizumab therapy. While resistance is commonly ascribed to tumor cell invasion induced by hypoxia-inducible factor (HIF), less attention has been paid to the potential involvement of endothelial cells (ECs) in vasculature activated by anti-angiogenic drugs. Methods: Human umbilical vein ECs (HUVECs), bEnd.3 cells, and mouse retinal microvascular ECs (MRMECs) were treated with bevacizumab under conditions of hypoxia and effects on biological behaviors, such as migration and tube formation, examined. Regulatory effects on TGFβ1 and CD105 (endoglin) were established via determination of protein and mRNA levels. We further investigated whether the effects of bevacizumab could be reversed using the receptor tyrosine kinase inhibitor anlotinib. Results: Bevacizumab upregulated TGFβ1 as well as CD105, a component of the TGFβ receptor complex and an angiogenesis promoter. Elevated CD105 induced activation of Smad1/5, the inflammatory pathway and endothelial-mesenchymal transition. The migration ability of HUVECs was enhanced by bevacizumab under hypoxia. Upregulation of CD105 was abrogated by anlotinib, which targets multiple receptor tyrosine kinases including VEGFR2/3, FGFR1-4, PDGFRα/β, C-Kit, and RET. Conclusions: Bevacizumab promotes migration and tube formation of HUVECs via activation of the TGFβ1 pathway and upregulation of CD105 expression. Anlotinib reverses the effects of bevacizumab by inhibiting the above signals.

While urine has been considered as a useful bio-fluid for health monitoring, its dynamic changes to physical activity are not well understood. We examined urine\'s possible antitumor capability in response to medium-level, loading-driven physical activity. Urine was collected from mice subjected to 5-minute skeletal loading and human individuals before and after 30-minute step aerobics. Six cancer cell lines (breast, prostate, and pancreas) and a mouse model of the mammary tumor were employed to evaluate the effect of urine. Compared to urine collected prior to loading, urine collected post-activity decreased the cellular viability, proliferation, migration, and invasion of tumor cells, as well as tumor weight in the mammary fat pad. Detection of urinary volatile organic compounds and ELISA assays showed that the loading-conditioned urine reduced cholesterol and elevated dopamine and melatonin. Immunohistochemical fluorescent images presented upregulation of the rate-limiting enzymes for the production of dopamine and melatonin in the brain. Molecular analysis revealed that the antitumor effect was linked to the reduction in molecular vinculin-linked molecular force as well as the downregulation of the Lrp5-CSF1-CD105 regulatory axis. Notably, the survival rate for the high expression levels of Lrp5, CSF1, and CD105 in tumor tissues was significantly lowered in the Cancer Genome Atlas database. Collectively, this study revealed that 5- or 10-minute loading-driven physical activity was sufficient to induce the striking antitumor effect by activating the neuronal signaling and repressing cholesterol synthesis. The result supported the dual role of loading-conditioned urine as a potential tumor suppressor and a source of diagnostic biomarkers.

G-protein coupled receptor 4 (GPR4) acts as a proton-sensing receptor and plays a role in regulating angiogenesis. Endoglin/CD105 is a marker of cell proliferation in vascular endothelial cells, particularly in tumor vasculature cells. Although there have been several studies investigating angiogenesis in hepatocellular carcinoma (HCC), none have investigated the association between GPR4 and microvessel density (MVD)-CD105 in this type of cancer. In the present study, CD105 and GPR4 were found to be expressed in benign and malignant liver tissues by immunofluorescence staining and laser confocal microscopy. Compared with levels in benign tissues, CD105 and GPR4 were highly expressed in neoplastic tissues. Furthermore, the average fluorescence intensity of GPR4 and MVD-CD105 was positively correlated. GPR4 and CD105 were found to be co-localized in the vascular endothelium in tumor tissues. Furthermore, the expression of GPR4 was higher in the marginal region of tumor tissues compared with the central region. These findings suggest that the expression of GPR4 in tumor microvessels in HCC may be implicated in tumor angiogenesis and development. Furthermore, the association between the expression of GPR4 and the clinicopathological features of patients with HCC further suggests a role for GPR4 in tumor angiogenesis and growth. Overall, these results suggest the potential of GPR4 as a prognostic factor and as an antiangiogenic target in patients with HCC.