Congenital and adult heart diseases are the leading cause of death globally, contributing 32% of global deaths. In Singapore, Cardiovascular disease accounted for 31.4% of all deaths in 2022. Our laboratory studies the molecular mechanisms that regulate cardiovascular development, homeostasis, and disease. Our goal is to understand how signaling pathways and transcriptional networks regulate cardiovascular cell lineage differentiation and their interaction (epicardium-myocardium and myocardium-endocardium) during heart morphogenesis. Defects in these processes during embryonic development underlie congenital heart disease (e.g. LVNC) and may contribute to the development of diseases in adulthood. Our work aims for a better understanding of congenital human diseases of the heart by establishing mouse models for these disorders and delineating the molecular changes associated with them. Our long-term goal is to apply lessons learned from our developmental studies to better understand and treat cardiovascular diseases.
There is increasing evidence that molecules and signaling pathways required during embryonic development also play an important role in cardiac homeostasis and disease in adults. For example, in the adult heart, epicardial cells are generally quiescent. However, ischemic injury results in the reactivation of a fetal gene program in the adult epicardium leading to increased epicardial cell proliferation and differentiation into cardiac fibroblasts. Additional evidence suggests that epicardial activation also amplifies the inflammatory response after ischemic injury. In the ischemic heart, fibrosis-inflammation axis is a key pathological driver of cardiac dysfunction in heart failure. So, the identification of intrinsic factors in the epicardial cells and extrinsic factors from immune cells (e.g. macrophages) that activate the epicardium will stimulate new discoveries in biology and potential therapeutic strategies for ischemic injury-induced heart failure.
Selected Publications
(# equal contribution, * corresponding author)
Mia MM, Cibi DM, Binte Abdul Ghani SA, Singh A, Tee N, Sivakumar V, Bogireddi H, Cook SA, Mao J, Singh MK*. Loss of Yap/Taz in cardiac fibroblasts attenuates adverse remodeling and improves cardiac function. Cardiovascular Research. 2021 Jun 16:cvab205. doi: 10.1093/cvr/cvab205.
Bi-Lin KW, Seshachalam PV, Tuoc T, Stoykova A, Ghosh S, Singh MK*. Critical role of the BAF chromatin remodeling complex during murine neural crest development. PLoS Genetics. 2021 Mar 22;17(3):e1009446. doi: 10.1371/journal.pgen.1009446.
Mia MM, Cibi DM, Abdul Ghani SAB, Song W, Tee N, Ghosh S, Mao J, Olson EN, Singh MK*. YAP/TAZ deficiency reprograms macrophage phenotype and improves infarct healing and cardiac function after myocardial infarction. PLoS Biology. 2020 Dec 2;18(12):e3000941.
Cibi DM, Bi-Lin KW, Shekeran SG, Sandireddy R, Tee N, Singh A, Wu Y, Srinivasan DK, Kovalik JP, Ghosh S, Seale P, Singh MK*. Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure. Cell Reports. 2020 Oct 20;33(3):108288. (Cover Story)
Mia MM, Singh MK*. The Hippo Signaling Pathway in Cardiac Development and Diseases. Front Cell Dev Biol. 2019 Oct 1;7:211.
Sandireddy R, Cibi DM, Gupta P, Singh A, Tee N, Uemura A, Epstein JA, Singh MK*. Semaphorin 3E/PlexinD1 signaling is required for cardiac ventricular compaction. JCI Insight. 2019 Aug 22;4(16):e125908.
Cibi DM, Mia MM, Shekeran SG, Yun LS, Sandireddy R, Gupta P, Hota M, Sun L, Ghosh S, Singh MK*. Neural crest-specific deletion of splicing factor Rbfox2 leads to craniofacial abnormalities including cleft palate. Elife. 2019 Jun 26;8:e45418.
Singh A, Mia MM, Cibi DM, Arya AK, Bhadada SK, Singh MK*. Deficiency in the secreted protein Semaphorin3d causes abnormal parathyroid development in mice. J Biol Chem. 2019 May 24;294(21):8336-8347.
Greicius G, Kabiri Z, Sigmundsson K, Chao L, Bunte R, Singh MK, Virshup DM. PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo. PNAS. 2018 Apr 3;115(14):E3173-E3181.
Ramjee V, Li D, Manderfield LJ, Liu F, Engleka KA, Aghajanian H, Rodell CB, Lu W, Ho V, Wang T, Li Li, Singh A, Cibi DM, Burdick JA, Singh MK*, Jain R*, Epstein JA*. Epicardial Yap/Taz Orchestrate an Immune Suppressive Response following MI. J Clin Invest. 2017 Mar 1;127(3):899-911.
Singh A, Ramesh S, Cibi DM, Yun LS, Li J, Li L, Manderfield LJ, Olson EN, Epstein JA, Singh MK*. Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development. Cell Reports. 2016 May 17;15(7):1384-93.
Wang M, Sips P, Khin E, Rotival M, Sun X, Ahmed R, Widjaja AA, Schafer S1, Yusoff P, Choksi PK, Ko NS, Singh MK, Epstein D, Guan Y, Houštěk J, Mracek T, Nuskova H, Mikell B, Tan J, Pesce F, Kolar F, Bottolo L, Mancini M, Hubner N, Pravenec M, Petretto E, MacRae C, Cook SA. Wars2 is a determinant of angiogenesis. Nature Communications 2016 Jul 8; 7:12061.
Lee KY, Singh MK, Ussar S, Wetzel P, Hirshman MF, Goodyear LJ, Kispert A, Kahn CR. Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism. Nature Communications. 2015 Aug 24;6:8054.
Roca LT, Tsaalbi-Shtylik A, Jansen JJ, Singh MK, Epstein JA, Altunoglu U, Verzijl H, Soria L, van Beusekom E, Roscioli T, Iqbal Z, Gilissen C, Hoischen A, deBrouwer A, Erasmus C, Schubert D, Brunner H, Perez A, Marin F, Aroca P, Kayserili H, Carta A, de Wind N, Padberg G, van Bokhoven H. De novo mutations in PLXND1 and REV3L cause Möbius Syndrome. Nature Communications, 2015 June 12;6:7199.
Minchin JEN, Dahlman I, Harvey CJ, Mejhert N, Singh MK, Epstein JA, Arner P, Torres-Vazquez J, Rawls JF. PlexinD1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. PNAS, 2015 Apr 7;112(14):4363-8. (Cover Story)
Epstein JA, Aghajanian H and Singh MK*. Semaphorin signaling in cardiovascular development. Cell Metabolism. 2015 Feb 3;21(2):163-173. (Cover Story)
Degenhardt K#, Singh MK#, Aghajanian H#, Massera D, Wang Q, Li J, Li L, Choi C, Yzaguirre AD, Francey LF, Gallant E, Krantz ID, Gruber PJ, Epstein JA. Semaphorin3D signaling defects associated with anomalous pulmonary venous connections. Nature Medicine. 2013 Jun;19(6):760-5.
Singh MK, Epstein JA. Epicardium derived cardiac mesenchymal stem cells: expanding the outer limit of heart repair. Circulation Research, 2012 Mar 30;110(7):904-6.
Katz TC#, Singh MK#, Degenhardt K#, Rivera-Feliciano J, Johnson RL, Epstein JA and Tabin CJ. Distinct compartments of the proepicardial organ give rise to coronary vascular endothelial cells. Developmental Cell. 2012 Mar 13;22(3):639-50.
Zygmunt T, Gay CM, Blondelle J, Singh MK, Flaherty KM, Means PC, Herwig L, Krudewig A, Belting H, Affolter M, Epstein JA, Torres-Vázquez J. Semaphorin-PlexinD1 Signaling Limits Angiogenic Potential via the VEGF Decoy Receptor sFlt1. Developmental Cell. 2011 Aug 16;21(2):301-14.