Myocardial infarction is a leading cause of morbidity with loss of contractile performance precipitated by the limited capacity of heart muscle for self-renewal. The aptitude of embryonic stem cells for differentiation into cardiomyocytes provides an opportunity for regenerative repair. Indeed, the basis for therapeutic use of these quintessential stem cells lies in their inherent pluripotency, yet the distinct ability for multi-lineage differentiation carries the liability of neoplastic growth that outweighs benefit impeding reparative applications. The objective of this proposal is to hone stem cell plasticity in order to nullify malignancy-prone unguided differentiation for safe repair. Preliminary studies demonstrate the aptitude for definitive cardiogenic commitment of an embryonic stem cell population within the developing embryoid body, during a transient window of endoderm-directed cardiotrophic signaling, with the resulting specification of the mesoderm yielding a progenitor """"""""cardiopoietic"""""""" stem cell phenotype.
Aim #1 will (i) isolate this pro-cardiogenic population utilizing embryoid body-based stem cell differentiation, (ii)define its molecular identity, and (iii)determine its propensity for terminal cardiomyogenic transformation.
Aim #2 will (i) decipher the endoderm-derived cardiotrophic signaling, (ii) recruit in an embryoid body-free manner the pro-cardiogenic cardiopoietic population at large scale, and (iii) validate in vivo the safety profile of this novel stem cell type.
Aim #3 will (i) assess the curative potential of procured cardiopoietic stem cells in treating myocardial infarction,(ii) determine the underlying mechanism for repair, and (iii) engineer stem cells for augmented tolerance to stress achieving enhanced cardioprotective outcome. Based on the characterization of cardiopoietic stem cells and the profiling of cardiotrophic cues, this proposal will dissect the fundamental process of cardiopoiesis securing formative confinement of pluripotency. Dissection of cardiogenesis at the molecular and cellular level will be further integrated into a therapeutic paradigm, and translated to the organ and organism level for safe cell-based regenerative therapy of myocardial infarction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL083439-05
Application #
7753254
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Schwartz, Lisa
Project Start
2006-01-01
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$359,270
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Terzic, Andre; Behfar, Atta (2017) Posology for Regenerative Therapy. Circ Res 121:1213-1215
Terzic, Andre; Behfar, Atta (2016) Stem cell therapy for heart failure: Ensuring regenerative proficiency. Trends Cardiovasc Med 26:395-404
Faustino, Randolph S; Behfar, Atta; Groenendyk, Jody et al. (2016) Calreticulin secures calcium-dependent nuclear pore competency required for cardiogenesis. J Mol Cell Cardiol 92:63-74
Martinez-Fernandez, Almudena; Nelson, Timothy J; Reyes, Santiago et al. (2014) iPS cell-derived cardiogenicity is hindered by sustained integration of reprogramming transgenes. Circ Cardiovasc Genet 7:667-76
Waldman, S A; Terzic, A (2013) Systems-based discovery advances drug development. Clin Pharmacol Ther 93:285-7
Thatava, Tayaramma; Kudva, Yogish C; Edukulla, Ramakrishna et al. (2013) Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther 21:228-39
Behfar, Atta; Latere, Jean-Pierre; Bartunek, Jozef et al. (2013) Optimized delivery system achieves enhanced endomyocardial stem cell retention. Circ Cardiovasc Interv 6:710-8
Folmes, Clifford D L; Martinez-Fernandez, Almudena; Faustino, Randolph S et al. (2013) Nuclear reprogramming with c-Myc potentiates glycolytic capacity of derived induced pluripotent stem cells. J Cardiovasc Transl Res 6:10-21
Waldman, Scott A; Terzic, Andre (2013) Translational medicine individualizes healthcare discovery, development and delivery. Foreword. Biomark Med 7:1-3
Waldman, S A; Terzic, A (2013) Information hierarchies optimize patient-centered solutions. Clin Pharmacol Ther 93:3-7

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