Heart failure is a major cause of premature death and disability in the United States. Adult-derived stem cells could provide a basis for effective therapies. This proposal is based on our finding that a well characterized adult-derived stem cell line (WB-F344), isolated from the adult rat liver, differentiates in vivo in the adult heart into heart cells. We will use the WB-F344 stem cell line and Fischer 344 (F344) rats in the normal heart and left anterior descending (LAD) coronary artery ligation model. We will test:Hypothesis 1. WB-F344 cells engraft in the heart, acquire a structural cardiac phenotype, and differentiate into mature cardiac myocytes in vivo. These processes will be affected by the different host cardiac microenvironments in the two models. We will examine these processes qualitatively and quantitatively. B-galactosidase activity will be used to identify WB-F344-derived myocytes. The commitment to a cardiac lineage and acquisition of a cardiac phenotype will be examined using expression of transcription factors, myofilament proteins, and membrane proteins and the remodeling of anatomical couplings, and their distribution. Hypothesis 2. WB-F344-derived myocytes acquire the functional phenotype of adult cardiac myocytes. These functional properties will be affected by the host cardiac microenvironments in the two models. We will examine the mechanical and electrophysiological properties of isolated single WB-F344-derived myocytes and host myocytes in vitro and their communication with host cells in situ. Hypothesis 3. WB-F344-derived cardiac myocytes affect ventricular function in vivo. Left ventricular dysfunction in the post myocardial infarction heart will be moderated by WB-F344-derived myocytes. The effects of WB-F344 cell engraftment and differentiation on in vivo left ventricular function and size will be examined, using echocardiography and cardiac catheterization. The proposed studies will provide new and important information about the functional properties of stem cell-derived cardiac myocytes and the potential value of stem cell-based approaches to treating heart failure.
| Lounes, Karim C; Demeler, Borries; Anderson, David E et al. (2008) Cardiac troponin T forms a tetramer in vitro. Biochemistry 47:1970-6 |
| Muller-Borer, Barbara J; Cascio, Wayne E; Esch, Gwyn L et al. (2007) Mechanisms controlling the acquisition of a cardiac phenotype by liver stem cells. Proc Natl Acad Sci U S A 104:3877-82 |
| Anderson, Page A W; Muller-Borer, Barbara J; Esch, Gwyn L et al. (2007) Calcium signals induce liver stem cells to acquire a cardiac phenotype. Cell Cycle 6:1565-9 |
| Nassar, Rashid; Malouf, Nadia N; Mao, Lan et al. (2005) cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform. Am J Physiol Heart Circ Physiol 288:H1147-56 |
