Progenitor Cell Therapeutics for Atherosclerotic Disease

Faculty

Thomas J. Povsic, MD, PhD Director

The main goals of our laboratory are:

Understanding the roles pf progenitor cells in maintaining vascular integrity
Exploring the possible uses of progentitor cell as therapeutics in the treatment of atherosclerotic heart disease and myocardial infarction

It is now appreciated that atherosclerosis is not simply a progressive disease of continual vascular damage, but represents a balance between chronic vascular injury accelerated by conventional risk factors and vascular repair mediated by endogenous progenitor cells (EPCs). Progenitor cells have been found both in the peripheral circulation and in the bone marrow.

Our laboratory has developed novel, more precise and more reliable techniques for measurement of circulating EPCs in patients. Our goal is to determine the underlying mechanisms responsible for progenitor cell depletion and loss of progenitor cell function, which play a key role in the exhaustion of reparative capacity that precedes the development of overt cardiovascular disease.

To study this problem, we have begun to construct a large database of circulating progenitor cell counts in patients undergoing cardiac catheterization. Taking advantage of the Duke Cardiovascular Database, we will correlate findings about EPC numbers and function with clinical variables to gain a better understanding of the relationship between reparative capacity and clinical outcomes.

Other areas of focus include:

The role of EPC mobilization in recovery after coronary artery bypass surgery: By partering with cardiovascular surgery and anesthesia, we have the opportunity to sample bone marrow at time of median sternotomy, allowing us to correlate bone marrow progenitor cell content to EPC numbers and peripheral cytokine levels. This allows us to assess the effect of chronic vascular injury on the body’s ability to mobilize reparative mechanisms at time of injury and to investigate the mechanisms responsible for loss of EPCs in the elderly and those with advanced disease.

The role of progenitor cell depletion in the aging process: In collaboration with orthopedic surgery, we are obtaining bone marrow specimens from patients undergoing elective orthopedic procedures. We will use these samples to assess the role of age and vascular disease on bone marrow progenitor cell composition.

Exploring the molecular pathways responsible for impairment of EPC function using gene expression analysis: We seek to identify particular pathways which are responsible for the loss of reparative capacity that occurs in the presence of long exposure to cardiac risk factors. Augmentation of such reparative capacity via pharmaceutical intervention aimed at reestablishing progenitor cell numbers and function offers a promising therapeutic option to not only limit further vascular damage, but to regenerate the vasculature.

Investigating the use of cellular therapies to treat a variety of cardiovascular conditions, including myocardial infarction in large animal models, a model uniquely suited to study intracoronary administration of cellular therapeutics.