title: Thromboxane Governs the Differentiation of Adipose-Derived Stromal Cells Toward Endothelial Cells In Vitro and In Vivo.
abstract: BACKGROUND
  Autologous adipose-derived stromal cells (ASCs) offer great promise as angiogenic cell therapy for ischemic diseases. Because of their limited self-renewal capacity and pluripotentiality, the therapeutic efficacy of ASCs is still relatively low. Thromboxane has been shown to play an important role in the maintenance of vascular homeostasis. However, little is known about the effects of thromboxane on ASC-mediated angiogenesis.
  
  
  OBJECTIVE
  To explore the role of the thromboxane-prostanoid receptor (TP) in mediating the angiogenic capacity of ASCs in vivo.
  
  
  RESULTS
  ASCs were prepared from mouse epididymal fat pads and induced to differentiate into endothelial cells (ECs) by vascular endothelial growth factor. Cyclooxygenase-2 expression, thromboxane production, and TP expression were upregulated in ASCs on vascular endothelial growth factor treatment. Genetic deletion or pharmacological inhibition of TP in mouse or human ASCs accelerated EC differentiation and increased tube formation in vitro, enhanced angiogenesis in in vivo Matrigel plugs and ischemic mouse hindlimbs. TP deficiency resulted in a significant cellular accumulation of β-catenin by suppression of calpain-mediated degradation in ASCs. Knockdown of β-catenin completely abrogated the enhanced EC differentiation of TP-deficient ASCs, whereas inhibition of calpain reversed the suppressed angiogenic capacity of TP re-expressed ASCs. Moreover, TP was coupled with Gαq to induce calpain-mediated suppression of β-catenin signaling through calcium influx in ASCs.
  
  
  CONCLUSIONS
  Thromboxane restrained EC differentiation of ASCs through TP-mediated repression of the calpain-dependent β-catenin signaling pathway. These results indicate that TP inhibition could be a promising strategy for therapy utilizing ASCs in the treatment of ischemic diseases.
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Shengkai
authors.initials: S
authors.lastname: Zuo
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Yuanyang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Hongfei
authors.initials: H
authors.lastname: Shi
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Shuai
authors.initials: S
authors.lastname: Yan
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Gong
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Deping
authors.initials: D
authors.lastname: Kong
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Luheng
authors.initials: L
authors.lastname: Lu
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Yu
authors.initials: Y
authors.lastname: Yu
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Sheng-Zhong
authors.initials: SZ
authors.lastname: Duan
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Claudio
authors.initials: C
authors.lastname: Schneider
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.).
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.affiliation: From the Key Laboratory of Food Safety Research, CAS Center for Excellence in Molecular Cell Science, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China (Y.S., S.Z., Y.W., S.Y., D.C., B.X., J.Z., Y.G., M.S., J.T., D.K., L.L., Y.Y., B.Z., S.-Z.D., Y.Y.); Department of Nutrition, The NO.2 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, China (Y.S., H.S.); Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, AREA Science Park, Trieste, Italy (C.S.); Dipartimento di Scienze e Tecnologie Biomediche, Università di Udine, Udine, Italy (C.S.); and Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada (C.D.F.). yuying@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000096:biosynthesis*; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013931:Thromboxanes / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013931:Thromboxanes; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin
keywords: adipose-derived stromal cell; angiogenesis; calcium; calpain; thromboxane receptor