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Receptor type protein tyrosine phosphatase-sigma (PTPsigma) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPsigma is also expressed by hematopoietic stem cells (HSCs). Here,we describe small molecule inhibitors of PTPsigma that promote HSC regeneration in vivo. Systemic administration of the PTPsigma inhibitor,DJ001,or its analog,to irradiated mice promotes HSC regeneration,accelerates hematologic recovery,and improves survival. Similarly,DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPsigma and antagonizes PTPsigma via unique non-competitive,allosteric binding. Mechanistically,DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase,RAC1,and induction of BCL-XL. Furthermore,treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective,small-molecule PTPsigma inhibitors for human hematopoietic regeneration. View Publication

Both anti-tumoral and pro-tumoral effects of mesenchymal stem cells (MSCs) in preclinical treatment of ovarian cancer have been controversially demonstrated. In this study,we profiled the phenotypes of mouse compact bone-derived MSCs (CB-MSCs) and bone marrow-derived MSCs (BM-MSCs) and found that CB-MSCs expressed lower CD90 compared to BM-MSCs. We examined gene expression of immune regulating cytokines of CB-MSCs in 2D and 3D culture and under stimulation with TLR4 agonist LPS or immune activator VIC-008. Our data showed that when CB-MSCs were cultured in simulated in vivo 3D condition,CD90 expression was further decreased. Moreover,gene expressions of immune activating cytokines IL-12,IL-21,IFNgamma and a pro-inflammatory cytokine CXCL10 in CB-MSCs were increased in 3D culture whereas gene expression of anti-inflammatory cytokines IL-10 and CCL5 were downregulated. Stimulation of CB-MSCs by LPS or VIC-008 presented similar profile of the cytokine gene expressions to that in 3D culture which might benefit the anti-tumor efficacy of CD90low MSCs. The anti-tumor effects of CD90low CB-MSCs alone or in combination with VIC-008 were evaluated in a syngeneic orthotopic mouse model of ovarian cancer. Treatment that combines CB-MSCs and VIC-008 significantly decreased tumor growth and prolonged mouse survival. This was associated with the increase of activated anti-tumoral CD4+ and CD8+ T cells and the decrease of Treg cells in the tumor microenvironment. Taken together,our study demonstrates the synergistic anti-tumoral efficacy by application of CB-MSCs combined with immune activator VIC-008 and provides new insight into CD90low MSCs as a new anti-tumor arsenal. View Publication

Background and Aims Epithelial expression of the insulin receptor in the colon has previously been reported to correlate with extent of colonic inflammation. However,the impact of insulin signalling in the intestinal mucosa is still unknown. Here,we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract,in an experimental model of inflammation-induced colorectal cancer. Methods The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing [vil-Cre-INSR+/-] × [INSRfl/fl] to obtain [vil-Cre-INSR-/-],and their floxed littermates [INSRfl/fl] served as the control group. For the intervention study,phosphate-buffered saline with or without insulin was instilled rectally in anaesthetized wild-type mice with chemically induced colitis. Results We found higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore,we showed that topically administered insulin in inflamed colons of wild-type mice reduced inflammation-induced weight loss and improved remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and reduced cyclooxygenase 2 mRNA expression,and developed significantly fewer and smaller tumours compared with the control group receiving phosphate-buffered saline only. Conclusions Rectal insulin therapy could potentially be a novel treatment,targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies. View Publication

Human adipose-derived stem cells (ADSCs) can release exosomes; however,their specific functions remain elusive. In this study,we verified that exosomes derived from osteogenically differentiated ADSCs can promote osteogenic differentiation of ADSCs. Furthermore,in order to investigate the importance of exosomal microRNAs (miRNAs) in osteogenic differentiation of ADSCs,we used microarray assays to analyze the expression profiles of exosomal miRNAs derived from undifferentiated as well as osteogenically differentiated ADSCs; 201 miRNAs were upregulated and 33 miRNAs were downregulated between the two types of exosomes. Additionally,bioinformatic analyses,which included gene ontology analyses,pathway analysis,and miRNA-mRNA-network investigations,were performed. The results of these analyses revealed that the differentially expressed exosomal miRNAs participate in multiple biological processes,such as gene expression,synthesis of biomolecules,cell development,differentiation,and signal transduction,among others. Moreover,we found that these differentially expressed exosomal miRNAs connect osteogenic differentiation to processes such as axon guidance,MAPK signaling,and Wnt signaling. To the best of our knowledge,this is the first study to identify and characterize exosomal miRNAs derived from osteogenically differentiated ADSCs. This study confirms that alterations in the expression of exosomal miRNAs can promote osteogenic differentiation of ADSCs,which also provides the foundation for further research on the regulatory functions of exosomal miRNAs in the context of ADSC osteogenesis. View Publication

Though lymphotoxin (LT) is highly expressed by type I helper T (Th1) cells,its contribution to CD4+ T cell differentiation during infections and diseases remains a mystery. In HSV-1 infection,we observed that LTbetaR signaling is required to limit the Th1 response. Using bone marrow chimeric mice,mixed-T-cell chimeric mice,and LTbetaR in vivo blockades,we unexpectedly observed that LT,especially T cell-derived LT,played an indispensable role in limiting the Th1 response. The LTbetaR-Ig blockade promoted the Th1 response by increasing infiltration of monocytes and monocyte-derived DCs and up-regulating IL-12 secretion in the lymphoid environment. Our findings identified a novel role for T cell-derived LT in manipulating Th1 differentiation. View Publication