Plasminogen regulates mesenchymal stem cell-mediated tissue repair after ischemia through Cyr61 activation.

Stem cell transplantation has emerged as a promising strategy in regenerative medicine. However, the poor survival and persistence of the transplanted cells, including mesenchymal stem cells (MSCs), in the hostile ischemic microenvironments represents a major therapeutic barrier. Here we report that plasminogen (Plg) stimulated MSC functions and promoted MSC survival during tissue repair after ischemia. Genetic Plg ablation abolished MSC survival, migration, and proliferation in mouse ischemic limbs, and abrogated MSC-mediated blood reperfusion, neovascularization, and tissue repair after ischemia, suggesting a critical role for Plg in MSC-mediated tissue repair. Furthermore, multiplex cytokine array analysis identified that Plg cleaved and activated cysteine-rich protein 61 (Cyr61), an ECM-associated growth factor, to stimulate MSC survival and migration. Overexpression with truncated Cyr61 in MSCs rescued blood reperfusion after hind limb ischemia in Plg-deficient mice. Finally, Plg-mediated Cyr61 cleavage promoted endothelial cell migration and neovascularization in vitro and in vivo. Our study reveals that Plg promotes MSC survival, persistence, and paracrine effects and improves postischemic neovascularization and tissue repair through Cyr61 cleavage and activation. Thus, targeting Plg/Cyr61 may offer exciting therapeutic opportunities for strengthening MSC therapy in ischemic diseases.

c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma.

Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.

CT Characterization of Duodenal Gastrointestinal Stromal Tumors.

OBJECTIVE: Diagnosis and staging of duodenal gastrointestinal stromal tumors (GISTs) by noninvasive imaging is critical for effective treatment, but the imaging features of duodenal GISTs remain largely undefined because of their rarity. The purpose of this article was to characterize duodenal GISTs using CT. MATERIALS AND METHODS: Thirty-four patients with duodenal GISTs were analyzed by clinical symptom evaluation, pathologic examination, and CT in this retrospective study. Unenhanced and contrast-enhanced examinations were performed in all patients. Imaging characteristics, including the lesion location, size, growth pattern, ulceration, internal components, arterial blood supply, intratumoral arterioportal shunting, intratumoral vessels, rim enhancement, and enhancement patterns were reviewed. RESULTS: The duodenal GISTs were solitary masses with well-defined margins. The average diameter was 7.1 cm. The second portion was the most common site (20/34). Ulceration was a common feature (15/34). Calcification was uncommon (3/34), and mixed growth pattern was more common (26/34). Rim enhancement (24/34) and mixed enhancement pattern (15/34) were common. Arterial blood supply, intratumoral vasculature, and draining veins were all detected and were obvious on the arterial phase. The portal venous trunk and superior mesenteric vein were the main veins into which early arterioportal shunting drained. CONCLUSION: Primary duodenal GISTs are generally large, well-defined, heterogeneously enhancing, and hypervascular masses with a prominent mixed growth pattern on CT images. Our findings suggest that CT can help depict the origin of the tumoral arteries and draining veins on the arterial phase and may be a key defining diagnostic feature for duodenal GISTs.