Advanced heart failure represents a major unmet clinical need, arising from the loss of viable or fully functional cardiac muscle cells. Despite optimum drug therapy, heart failure is a leading cause of mortality in America. Generating functional myocardial tissue from a renewable patient-specific source would allow for the development of disease specific cellular models for pathway identification and drug development. It would also lay the foundation for therapeutic cardiac regenerative medicine. We propose to integrate the unique expertise, reagents, and protocols from four leading laboratories in cardiac stem cell biology and development (Chien/Wu), human ES and IPS technology (Melton), and cardiac tissue engineering (Parker), to generate patient-specific myocardial tissue as cellular models for human cardiovascular disease, and as a foundation for cell-based regenerative therapy. Accordingly, the specific aims of our proposed project are the following.
AIM 1 : Identify non-cell autonomous signaling pathways that control cardiovascular progenitor cell (CVP) expansion and differentiation. We hypothesize that specific non-cell autonomous signaling pathways control murine CVP expansion and differentiation.
AIM 2 : Determine if murine iPS-derived CVPs recapitulate normal cardiac development and can be used to generate functional myocardial tissue in vitro. We hypothesize that IPS derived cardiac progenitors are similar to ESC-derived cardiac progenitors in developmental potential and functional characteristics.
AIM 3 : Isolate and characterize CVPs from human ES and IPS cells. We hypothesize that during human ES and iPS cell differentiation, cardiac myocytes are generated by the commitment of cardiac progenitors into CVPs which then differentiate into fully mature ventricular myocytes.
AIM 4 : Generate cellular models for human cardiovascular disease such as X-linked cardiomyopathy (i.e. cardiomyopathies caused by dystrophin mutations such as those in Duchenne's and Becker's muscular dystrophy). We hypothesize that disease specific CVP will recapitulate diseased myocardial phenotype, as well as diseased myocardial phenotype. This will serve as a platform for genetic pathway discovery, drug design, and regenerative cardiovascular medicine.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-J (S1))
Program Officer
Buxton, Denis B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Hu, Dongjian; Linders, Annet; Yamak, Abir et al. (2018) Metabolic Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes by Inhibition of HIF1? and LDHA. Circ Res 123:1066-1079
Atmanli, Ayhan; Domian, Ibrahim John (2017) Recreating the Cardiac Microenvironment in Pluripotent Stem Cell Models of Human Physiology and Disease. Trends Cell Biol 27:352-364
Pasqualini, F S; Emmert, M Y; Parker, K K et al. (2017) Organ Chips: Quality Assurance Systems in Regenerative Medicine. Clin Pharmacol Ther 101:31-34
Emmert, Maximilian Y; Wolint, Petra; Jakab, Andras et al. (2017) Safety and efficacy of cardiopoietic stem cells in the treatment of post-infarction left-ventricular dysfunction - From cardioprotection to functional repair in a translational pig infarction model. Biomaterials 122:48-62
Kijlstra, Jan David; Hu, Dongjian; van der Meer, Peter et al. (2017) Single-Cell Functional Analysis of Stem-Cell Derived Cardiomyocytes on Micropatterned Flexible Substrates. Curr Protoc Stem Cell Biol 43:1F.20.1-1F.20.9
Capulli, A K; MacQueen, L A; Sheehy, Sean P et al. (2016) Fibrous scaffolds for building hearts and heart parts. Adv Drug Deliv Rev 96:83-102
Aratyn-Schaus, Yvonne; Pasqualini, Francesco S; Yuan, Hongyan et al. (2016) Coupling primary and stem cell-derived cardiomyocytes in an in vitro model of cardiac cell therapy. J Cell Biol 212:389-97
Pope, Benjamin D; Warren, Curtis R; Parker, Kevin Kit et al. (2016) Microenvironmental Control of Adipocyte Fate and Function. Trends Cell Biol 26:745-755
Pacheco-Leyva, Ivette; Matias, Ana Catarina; Oliveira, Daniel V et al. (2016) CITED2 Cooperates with ISL1 and Promotes Cardiac Differentiation of Mouse Embryonic Stem Cells. Stem Cell Reports 7:1037-1049
Peters, Derek T; Henderson, Christopher A; Warren, Curtis R et al. (2016) Asialoglycoprotein receptor 1 is a specific cell-surface marker for isolating hepatocytes derived from human pluripotent stem cells. Development 143:1475-81

Showing the most recent 10 out of 60 publications