title: Overexpression of Gremlin1 in Mesenchymal Stem Cells Improves Hindlimb Ischemia in Mice by Enhancing Cell Survival.
abstract: Mesenchymal stem cells (MSCs) are a promising cell resource for the treatment of ischemic diseases, partially through paracrine effects. One of the major obstacles of MSC treatment is the poor survival rate and low efficiency of transplanted stem cells due to ischemic or inflammatory environments. Gremlin1 (GREM1), a regulator of growth, differentiation and development, has been identified as a novel proangiogenic factor. However, the role and mechanism of GREM1 in MSCs remains unclear. Therefore, we assessed the putative beneficial effects of GREM1 on MSC-based therapy for hindlimb ischemia. The lentiviral vector, EF1a-GREM1, was constructed using the Multisite Gateway System and used to transduce MSCs. In vitro studies demonstrated increased survival of GREM1-MSCs exposed to H2O2, which is consistent with the activation of caspase-3. Conditional medium from GREM1-MSCs (GREM1-MSC-CM) increased the anti-apoptotic effects of human umbilical vein endothelial cells (HUVECs), and this effect was attenuated by treatment with the PI3K/Akt pathway inhibitor LY294002. MSCs modified with GREM1 could significantly increase blood perfusion of the ischemic hindlimb in vivo in a mouse model, which was correlated to improved MSC survival. This study demonstrates that overexpression of GREM1 in MSCs have greater therapeutic effects against ischemia compared with wild-type MSCs by enhancing the survival of MSCs and ECs, which may provide new tools for studies investigating the treatment of ischemic diseases. J. Cell. Physiol. 232: 996-1007, 2017. © 2016 Wiley Periodicals, Inc.
authors: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.|Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Qiuling
authors: Q
authors: Xiang
authors: Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Dongxi
authors: D
authors: Hong
authors: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Yan
authors: Y
authors: Liao
authors: Cardiovascular Center, Gaozhou People's Hospital, Maoming, Guangdong, China.
authors: Yong
authors: Y
authors: Cao
authors: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Muyun
authors: M
authors: Liu
authors: Guizhou Provincial People's Hospital, Guizhou, China.
authors: Jun
authors: J
authors: Pang
authors: Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Junjie
authors: J
authors: Zhou
authors: Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China.
authors: Guang
authors: G
authors: Wang
authors: Division of Histology and Embryology, Medical College, Jinan University, Guangzhou, China.
authors: Renhao
authors: R
authors: Yang
authors: Cardiovascular Center, Gaozhou People's Hospital, Maoming, Guangdong, China.
authors: Maosheng
authors: M
authors: Wang
authors: Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong, China.|Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.|Biotherapy Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors: Andy Peng
authors: AP
authors: Xiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001160:Arterioles / Q000473:pathology; D002196:Capillaries / Q000473:pathology; D002470:Cell Survival; D002642:Chick Embryo; D004195:Disease Models, Animal; D005260:Female; D055785:Gene Knockdown Techniques; D006614:Hindlimb / Q000098:blood supply* / Q000473:pathology*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007511:Ischemia / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012039:Regional Blood Flow; D015398:Signal Transduction; D014019:Tissue Donors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt