An important issue in need of resolution concerns whether myocyte regeneration in the adult heart is controlled exclusively by activation and commitment of resident c-kit-positive cardiac stem cells (CSCs), or circulating hematopoietic stem cells (HSCs) from the bone marrow contribute to cardiomyogenesis. Although CSCs divide asymmetrically being able to self-renew and form a specialized progeny, whether this stem cell compartment is fully independent from the pool of HSCs in regulating cardiac homeostasis remains controversial. In an attempt to resolve this biological problem, bone marrow transplantation and a model of parabiosis will be employed to establish quantitatively the relative role of HSCs and CSCs in myocyte renewal in adulthood and in tissue regeneration following ischemic myocardial injury. An additional complementary question is whether stem cells in the niches are all of cardiac origin or HSCs migrate from the bone marrow to the myocardial niches where they attain a new identity participating in the turnover of these primitive cells in their microenvironment. If this were the case, HSCs would be involved in the preservation of the stem cell pool in the heart, which constitutes the growth reserve of the myocardium throughout the course of life. A common mechanism involving oscillations in intracellular Ca2+, cell cycle entry, asymmetric division, and nuclear shuttling of the myocyte transcription factor Nkx2.5 is postulated to regulate the lineage specification of CSCs and HSCs into cardiomyocytes. Ultimately, the molecular mechanisms of HSC transdifferentiation will be identified and the involvement of the bone marrow in cardiomyogenesis carefully defined.

Public Health Relevance

This research aims at the identification and quantification of the celular proceses that regulate cardiac homeostasis and myocardial regeneration following ischemic injury. Both CSCs and HSCs are postulated to contribute to myocyte regeneration physiologically and after myocardial infarction. If successful, novel strategies for the treatment f the diseased heart may be identified.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL114346-03
Application #
8649080
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Goichberg, Polina; Chang, Jerway; Liao, Ronglih et al. (2014) Cardiac stem cells: biology and clinical applications. Antioxid Redox Signal 21:2002-17
Rota, Marcello; Leri, Annarosa; Anversa, Piero (2014) Human heart failure: is cell therapy a valid option? Biochem Pharmacol 88:129-38
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João et al. (2014) Response to letter regarding article "Inositol 1,4,5-trisphosphate receptors and human left ventricular myocytes". Circulation 129:e510-1
Leri, Annarosa; Rota, Marcello; Hosoda, Toru et al. (2014) Cardiac stem cell niches. Stem Cell Res 13:631-46
Sanada, Fumihiro; Kim, Junghyun; Czarna, Anna et al. (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41-55
D'Amario, Domenico; Leone, Antonio M; Iaconelli, Antonio et al. (2014) Growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery. Circulation 129:157-72
Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, Joao et al. (2013) Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation 128:1286-97
Goichberg, Polina; Kannappan, Ramaswamy; Cimini, Maria et al. (2013) Age-associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128:2211-23
Leri, Annarosa; Anversa, Piero (2013) Stem cells and myocardial regeneration: cooperation wins over competition. Circulation 127:165-8
Schoenfeld, Matthew; Frishman, William H; Leri, Annarosa et al. (2013) The existence of myocardial repair: mechanistic insights and enhancements. Cardiol Rev 21:111-20