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Stem cell therapy research has gained ground in CV medicine
Data have demonstrated that progenitor cells could be used for diagnostic and prognostic purposes, but remaining questions need answers.
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The recent demonstrations that animal hearts and human trachea can be recellularized using stem cells have accelerated the already growing interest in stem cell therapy for the cardiovascular system.
Stem cells from bone marrow and other sites (collectively, progenitor cells) maintain CV structure and function. The progenitor cell levels and function fluctuate in response to clinical situations. Progenitor cells will mobilize from bone marrow (and possibly tissue-resident sources) in response to triggers like ischemia and infarction, to initiate repair through angiogenesis and cardiomyocyte regeneration. Direct trauma to endothelium seems to elicit a similar response.
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These responses are mediated via a number of signaling molecules which are sensed by bone marrow to increase the number and type of progenitor cells mobilized to the circulation and locally. An increase in progenitor cells is also associated with selected small molecules used for CV therapy (statins, ACE/angiotensin receptor blockers) and even exercise; and there is a negative association between the presence and intensity of CV risk conditions, ie, diabetes, aging, smoking, hypertension, etc. This suggests that progenitor cells may be a useful exvivo prognostic marker in patients with clinically established disease like atherosclerosis and perhaps even those destined to develop clinical CVD (ie, at high risk). It may be possible to use these cells for diagnostic and prognostic purposes and even to predict response to therapy in a given individual. Thus, there are even possibilities for individualized medicine using a cell-based monitoring approach.
What’s the potential?
The question of how the cells used for cell therapy may actually enhance vascular repair and neovascularization has not been answered satisfactorily. Evidence suggests that progenitor cell incorporation into the vasculature and myocardium is infrequent, if at all. However, these cells produce angiogenic factors and chemoattractants with the potential to encourage mobilization of circulating and local progenitor cells to the injured region. Their therapeutic usefulness is being investigated in clinical trials using bone marrow cells and circulating cell populations enriched in progenitor cells mobilized from bone marrow after stimulation with G-CSF that are obtained from peripheral blood by apheresis.
Patient studies are proceeding at a very rapid pace worldwide, and many companies have announced programs in CV regenerative medicine. A majority of the large number of completed randomized controlled trials, which now collectively contain >2,000 patients, have focused in acute or recent MI (>1,000 patients). Results from these latter studies are of particular interest because, when considered together, they demonstrate a signal suggesting potential clinical benefit (ie, a small increase in ejection fraction). A few trials have even reported improved short-term (from four months up to one year) clinical outcomes manifest as fewer deaths or hospitalizations for revascularization or HF. Perhaps more importantly at this stage in cell therapy development, these results also consistently document relative safety among the cell-treated patient cohorts compared with controls.
However, these early results have also generated numerous questions. Almost all studies to date have used bone marrow cells or bone marrow cells mobilized to peripheral blood given via direct intracoronary injection. Thus, these randomized controlled trials have not provided the information needed to determine the optimal cell type, dosing (ie, single or multiple and cell number and timing) or delivery method (ie, intracoronary vs. intramyocardial vs. coronary veins), response measures (ie, perfusion vs. left ventricular function, etc.) or specific target populations (ie, early after MI, late after MI, CHF, refractory angina, etc.). Techniques of harnessing the potential of progenitor cells include enhancing the resident population (increasing numbers and function) by drugs or genetic modification or exvivo cell enhancement before injection. Other novel approaches include enhancing the target tissue (ie, low dose shockwave exposure) to express SDF-1 and VEGF so that cell attraction is increased.
Despite their obvious potential in clinical practice, a very large number of important questions remain unanswered at both the basic science and clinical science level. It has been only about 10 years since the seminal report of circulating CV progenitor cells and already the stem cell has gained a unique position at the frontier of CV medicine. My prediction is that this interest will continue to grow for the foreseeable future.
Carl J. Pepine, MD, is a Professor in the Division of Cardiovascular Medicine, University of Florida, Gainesville. He is Chief Medical Editor of Cardiology Today.
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