NIH Symposium: Challenges & Promise of Cell-Based Therapies
May 6, 2008
Natcher Conference Center
NIH Main Campus, Bethesda, Maryland
Session 2: Cardiac Disorders
Moderator: Sonia Skarlatos, Ph.D.; National Heart, Lung, and Blood Institute, NIH
|Cardiac Progenitor Cells and Aging Myopathy
Annarosa Leri, M.D.; Harvard Medical School
Dr. Leri began by noting that cardiomyopathy due to aging is dictated by the depletion of the resident cardiac progenitor cell (CPC) pool and the accumulation of old myocytes. CPCs give rise to myocyte progenitor cells, which then become myocyte precursors, and, ultimately, myocytes. Myocardial aging either affects all CPCs uniformly or a subset of functionally-competent CPCs persists in the senescent heart. The effects of aging on cardiac remodeling can be reversed by activation, mobilization, and differentiation of resident CPCs that may ultimately repair the decompensated senescent heart.
When measuring the number of CPCs in rat heart via expression of p16INK4a, it is observed that the number of functionally-competent CPC remains stable through 20 months but decreases rapidly thereafter. The expansion of the CPC compartment with age is characterized by the accumulation of old, non-replicating, dying p16-positive cells. The senescent heart also contains a pool of functionally-competent CPCs which, upon activation, retain the ability to form new myocytes. Telomere attrition in CPCs with age leads to the generation of a myocyte progeny that rapidly acquires the senescent phenotype that characterizes organ aging. Aging negatively affects the growth factor systems involved in CPC proliferation and survival, thereby potentiating the consequences of the local renin-angiotensin system on these cells. Myocardial aging, however, does not deplete the pool of functionally-competent CPCs. Treatment with growth factors leads to an increase in survival, indicating that the senescent heart contains a pool of functionally-competent CPCs that can be activated by growth factor administration to migrate and differentiate into mature myocytes, thereby converting a decompensated and senescent heart into a younger and more efficient organ.
One attendee asked Dr. Leri if her research group had investigated these observations in human cells, to which she responded that similar characteristics are observed. Another participant asked if the observed changes are related to the cells themselves or reflect responses to other cells in the niche. Dr. Leri noted that aging involves both processes, which ultimately promote a down-regulation of growth factors with age.