PMID- 28978553 OWN - NLM STAT- MEDLINE DCOM- 20171204 LR - 20200520 IS - 1524-4539 (Electronic) IS - 0009-7322 (Print) IS - 0009-7322 (Linking) VI - 136 IP - 22 DP - 2017 Nov 28 TI - C1q/Tumor Necrosis Factor-Related Protein-9 Regulates the Fate of Implanted Mesenchymal Stem Cells and Mobilizes Their Protective Effects Against Ischemic Heart Injury via Multiple Novel Signaling Pathways. PG - 2162-2177 LID - 10.1161/CIRCULATIONAHA.117.029557 [doi] AB - BACKGROUND: Cell therapy remains the most promising approach against ischemic heart injury. However, the poor survival of engrafted stem cells in the ischemic environment limits their therapeutic efficacy for cardiac repair after myocardial infarction. CTRP9 (C1q/tumor necrosis factor-related protein-9) is a novel prosurvival cardiokine with significantly downregulated expression after myocardial infarction. Here we tested a hypothesis that CTRP9 might be a cardiokine required for a healthy microenvironment promoting implanted stem cell survival and cardioprotection. METHODS: Mice were subjected to myocardial infarction and treated with adipose-derived mesenchymal stem cells (ADSCs, intramyocardial transplantation), CTRP9, or their combination. Survival, cardiac remodeling and function, cardiomyocytes apoptosis, and ADSCs engraftment were evaluated. Whether CTRP9 directly regulates ADSCs function was determined in vitro. Discovery-drive approaches followed by cause-effect analysis were used to uncover the molecular mechanisms of CTRP9. RESULTS: Administration of ADSCs alone failed to exert significant cardioprotection. However, administration of ADSCs in addition to CTRP9 further enhanced the cardioprotective effect of CTRP9 (P<0.05 or P<0.01 versus CTRP9 alone), suggesting a synergistic effect. Administration of CTRP9 at a dose recovering physiological CTRP9 levels significantly prolonged ADSCs retention/survival after implantation. Conversely, the number of engrafted ADSCs was significantly reduced in the CTRP9 knockout heart. In vitro study demonstrated that CTRP9 promoted ADSCs proliferation and migration, and it protected ADSCs against hydrogen peroxide-induced cellular death. CTRP9 enhances ADSCs proliferation/migration by extracellular regulated protein kinases (ERK)1/2-matrix metallopeptidase 9 signaling and promotes antiapoptotic/cell survival via ERK-nuclear factor erythroid-derived 2-like 2/antioxidative protein expression. N-cadherin was identified as a novel CTRP9 receptor mediating ADSCs signaling. Blockade of either N-cadherin or ERK1/2 completely abolished the previously noted CTRP9 effects. Although CTRP9 failed to promote ADSCs cardiogenic differentiation, CTRP9 promotes superoxide dismutase 3 expression and secretion from ADSCs, protecting cardiomyocytes against oxidative stress-induced cell death. CONCLUSIONS: We provide the first evidence that CTRP9 promotes ADSCs proliferation/survival, stimulates ADSCs migration, and attenuates cardiomyocyte cell death by previously unrecognized signaling mechanisms. These include binding with N-cadherin, activation of ERK-matrix metallopeptidase 9 and ERK-nuclear factor erythroid-derived 2-like 2 signaling, and upregulation/secretion of antioxidative proteins. These results suggest that CTRP9 is a cardiokine critical in maintaining a healthy microenvironment facilitating stem cell engraftment in infarcted myocardial tissue, thereby enhancing stem cell therapeutic efficacy. CI - (c) 2017 American Heart Association, Inc. FAU - Yan, Wenjun AU - Yan W AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China (W.Y., L.T.). FAU - Guo, Yongzhen AU - Guo Y AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Tao, Ling AU - Tao L AD - Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China (W.Y., L.T.). FAU - Lau, Wayne Bond AU - Lau WB AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Gan, Lu AU - Gan L AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Yan, Zheyi AU - Yan Z AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Guo, Rui AU - Guo R AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Gao, Erhe AU - Gao E AD - Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.L.K.). FAU - Wong, G William AU - Wong GW AD - Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD (G.W.W.). FAU - Koch, Walter L AU - Koch WL AD - Center for Translational Medicine, Temple University, Philadelphia, PA (E.G., W.L.K.). FAU - Wang, Yajing AU - Wang Y AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). FAU - Ma, Xin-Liang AU - Ma XL AD - Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (W.Y., Y.G., W.B.L., L.G., Z.Y., R.G., Y.W., X.-L.M.). xin.ma@jefferson.edu yajing.wang@jefferson.edu. LA - eng GR - S10 OD010408/OD/NIH HHS/United States GR - R01 HL096686/HL/NHLBI NIH HHS/United States GR - R01 HL123404/HL/NHLBI NIH HHS/United States GR - R56 HL123404/HL/NHLBI NIH HHS/United States GR - R01 DK084171/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20171004 PL - United States TA - Circulation JT - Circulation JID - 0147763 RN - 0 (Adiponectin) RN - 0 (CTRP9 protein, mouse) RN - 0 (Cadherins) RN - 0 (Cdh2 protein, mouse) RN - 0 (Glycoproteins) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Nfe2l2 protein, mouse) RN - 0 (enhanced green fluorescent protein) RN - 147336-22-9 (Green Fluorescent Proteins) RN - BBX060AN9V (Hydrogen Peroxide) RN - EC 1.15.1.1 (Sod3 protein, mouse) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM MH - Adiponectin/administration & dosage/deficiency/genetics/*metabolism MH - Adipose Tissue/cytology MH - Animals MH - Apoptosis MH - Cadherins/metabolism MH - Cell Movement MH - Cell Proliferation MH - Cells, Cultured MH - Disease Models, Animal MH - Extracellular Signal-Regulated MAP Kinases/metabolism MH - Fibrosis MH - Glycoproteins/administration & dosage/deficiency/genetics/*metabolism MH - Green Fluorescent Proteins/genetics MH - Hydrogen Peroxide/toxicity MH - Male MH - Matrix Metalloproteinase 9/metabolism MH - Mesenchymal Stem Cell Transplantation MH - Mesenchymal Stem Cells/drug effects/*metabolism MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Transgenic MH - Myocardial Infarction/metabolism/pathology/physiopathology/*prevention & control MH - Myocytes, Cardiac/drug effects/*metabolism/pathology MH - NF-E2-Related Factor 2/metabolism MH - Phenotype MH - *Regeneration/drug effects MH - *Signal Transduction/drug effects MH - Stem Cell Niche MH - Superoxide Dismutase/metabolism MH - Time Factors PMC - PMC5705403 MID - NIHMS911582 OTO - NOTNLM OT - N-cadherin OT - cardiokines OT - ischemic heart injury OT - stem cell EDAT- 2017/10/06 06:00 MHDA- 2017/12/05 06:00 PMCR- 2018/11/28 CRDT- 2017/10/06 06:00 PHST- 2017/05/19 00:00 [received] PHST- 2017/09/14 00:00 [accepted] PHST- 2017/10/06 06:00 [pubmed] PHST- 2017/12/05 06:00 [medline] PHST- 2017/10/06 06:00 [entrez] PHST- 2018/11/28 00:00 [pmc-release] AID - CIRCULATIONAHA.117.029557 [pii] AID - 10.1161/CIRCULATIONAHA.117.029557 [doi] PST - ppublish SO - Circulation. 2017 Nov 28;136(22):2162-2177. doi: 10.1161/CIRCULATIONAHA.117.029557. Epub 2017 Oct 4.