Insulin-Like Growth Factor 1 Receptor-Dependent Pathway Drives Epicardial Adipose Tissue Formation After Myocardial Injury.
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.
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.
Lior
L
Zangi
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.).
Marcela S
MS
Oliveira
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.).
Lillian Y
LY
Ye
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.).
Qing
Q
Ma
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.).
Nishat
N
Sultana
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.).
Yoav
Y
Hadas
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.).
Elena
E
Chepurko
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.).
Daniela
D
Später
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.).
Bin
B
Zhou
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.).
Wei Leong
WL
Chew
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.).
Wataru
W
Ebina
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.).
Maryline
M
Abrial
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.).
Qing-Dong
QD
Wang
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.
William T
WT
Pu
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.
Kenneth R
KR
Chien
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D010496:Pericardium / Q000166:cytology*; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D025721:WT1 Proteins
D012097:Repressor Proteins; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1
Wt1; epicardial adipose tissue; epicardium; insulin-like growth factor-1; myocardial infarction