Lior Zangi1, Marcela S Oliveira2, Lillian Y Ye2, Qing Ma2, Nishat Sultana2, Yoav Hadas2, Elena Chepurko2, Daniela Später2, Bin Zhou2, Wei Leong Chew2, Wataru Ebina2, Maryline Abrial2, Qing-Dong Wang2, William T Pu1, Kenneth R Chien1. 1. From Cardiovascular Research Center, Department of Genetics and Genomic Sciences, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York (L.Z., N.S., Y.H.); Department of Cardiology, Boston Children's Hospital, MA (L.Z., M.S.O., L.Y.Y., Q.M., W.T.P.); Cardiovascular and Metabolic Diseases Innovative Medicine Biotech Unit, AstraZeneca, Möllndal, Sweden (D.S., Q.-D.W.); The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (B.Z.); Department of Genetics (W.L.C.), Harvard Stem Cell Institute (W.E., W.T.P.), Harvard Medical School, and Cardiovascular Research Center, Massachusetts General Hospital (M.A.), Harvard Medical School, Boston, MA; and Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, Stockholm, Sweden (K.R.C.). lior.zangi@mssm.edu wpu@pulab.org kenneth.chien@ki.se. 2. From Cardiovascular Research Center, Department of Genetics and Genomic Sciences, and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York (L.Z., N.S., Y.H.); Department of Cardiology, Boston Children's Hospital, MA (L.Z., M.S.O., L.Y.Y., Q.M., W.T.P.); Cardiovascular and Metabolic Diseases Innovative Medicine Biotech Unit, AstraZeneca, Möllndal, Sweden (D.S., Q.-D.W.); The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (B.Z.); Department of Genetics (W.L.C.), Harvard Stem Cell Institute (W.E., W.T.P.), Harvard Medical School, and Cardiovascular Research Center, Massachusetts General Hospital (M.A.), Harvard Medical School, Boston, MA; and Department of Cell and Molecular Biology and Medicine, Karolinska Institutet, Stockholm, Sweden (K.R.C.).
Abstract
BACKGROUND: Epicardial adipose tissue volume and coronary artery disease are strongly associated, even after accounting for overall body mass. Despite its pathophysiological significance, the origin and paracrine signaling pathways that regulate epicardial adipose tissue's formation and expansion are unclear. METHODS: We used a novel modified mRNA-based screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the adult heart. RESULTS: Using 2 independent lineage-tracing strategies in murine models, we show that cells originating from the Wt1+ mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue after myocardial infarction. This differentiation process required Wt1 expression in this lineage and was stimulated by insulin-like growth factor 1 receptor (IGF1R) activation. IGF1R inhibition within this lineage significantly reduced its adipogenic differentiation in the context of exogenous, IGF1-modified mRNA stimulation. Moreover, IGF1R inhibition significantly reduced Wt1 lineage cell differentiation into adipocytes after myocardial infarction. CONCLUSIONS: Our results establish IGF1R signaling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury by redirecting the fate of Wt1+ lineage cells. Our study also demonstrates the power of modified mRNA -based paracrine factor library screening to dissect signaling pathways that govern progenitor cell activity in homeostasis and disease.
BACKGROUND: Epicardial adipose tissue volume and coronary artery disease are strongly associated, even after accounting for overall body mass. Despite its pathophysiological significance, the origin and paracrine signaling pathways that regulate epicardial adipose tissue's formation and expansion are unclear. METHODS: We used a novel modified mRNA-based screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the adult heart. RESULTS: Using 2 independent lineage-tracing strategies in murine models, we show that cells originating from the Wt1+ mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue after myocardial infarction. This differentiation process required Wt1 expression in this lineage and was stimulated by insulin-like growth factor 1 receptor (IGF1R) activation. IGF1R inhibition within this lineage significantly reduced its adipogenic differentiation in the context of exogenous, IGF1-modified mRNA stimulation. Moreover, IGF1R inhibition significantly reduced Wt1 lineage cell differentiation into adipocytes after myocardial infarction. CONCLUSIONS: Our results establish IGF1R signaling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury by redirecting the fate of Wt1+ lineage cells. Our study also demonstrates the power of modified mRNA -based paracrine factor library screening to dissect signaling pathways that govern progenitor cell activity in homeostasis and disease.
Authors: Lior Zangi; Kathy O Lui; Alexander von Gise; Qing Ma; Wataru Ebina; Leon M Ptaszek; Daniela Später; Huansheng Xu; Mohammadsharif Tabebordbar; Rostic Gorbatov; Brena Sena; Matthias Nahrendorf; David M Briscoe; Ronald A Li; Amy J Wagers; Derrick J Rossi; William T Pu; Kenneth R Chien Journal: Nat Biotechnol Date: 2013-09-08 Impact factor: 54.908
Authors: Bin Zhou; Leah B Honor; Huamei He; Qing Ma; Jin-Hee Oh; Catherine Butterfield; Ruei-Zeng Lin; Juan M Melero-Martin; Elena Dolmatova; Heather S Duffy; Alexander von Gise; Pingzhu Zhou; Yong Wu Hu; Gang Wang; Bing Zhang; Lianchun Wang; Jennifer L Hall; Marsha A Moses; Francis X McGowan; William T Pu Journal: J Clin Invest Date: 2011-04-18 Impact factor: 14.808
Authors: Nicola Smart; Catherine A Risebro; Athalie A D Melville; Kelvin Moses; Robert J Schwartz; Kenneth R Chien; Paul R Riley Journal: Nature Date: 2006-11-15 Impact factor: 49.962
Authors: You-Ying Chau; David Brownstein; Heidi Mjoseng; Wen-Chin Lee; Natalija Buza-Vidas; Claus Nerlov; Sten Eirik Jacobsen; Paul Perry; Rachel Berry; Anna Thornburn; David Sexton; Nik Morton; Peter Hohenstein; Elisabeth Freyer; Kay Samuel; Rob van't Hof; Nicholas Hastie Journal: PLoS Genet Date: 2011-12-22 Impact factor: 5.917
Authors: Yoav Hadas; Adam S Vincek; Elias Youssef; Magdalena M Żak; Elena Chepurko; Nishat Sultana; Mohammad Tofael Kabir Sharkar; Ningning Guo; Rinat Komargodski; Ann Anu Kurian; Keerat Kaur; Ajit Magadum; Anthony Fargnoli; Michael G Katz; Nadia Hossain; Ephraim Kenigsberg; Nicole C Dubois; Eric Schadt; Roger Hajjar; Efrat Eliyahu; Lior Zangi Journal: Circulation Date: 2020-01-29 Impact factor: 29.690