Stem cell therapy for cardiovascular disease: the demise of alchemy and rise of pharmacology

Abstract

Regenerative medicine holds great promise as a way of addressing the limitations of current treatments of ischaemic disease. In preclinical models, transplantation of different types of stem cells or progenitor cells results in improved recovery from ischaemia. Furthermore, experimental studies indicate that cell therapy influences a spectrum of processes, including neovascularization and cardiomyogenesis as well as inflammation, apoptosis and interstitial fibrosis. Thus, distinct strategies might be required for specific regenerative needs. Nonetheless, clinical studies have so far investigated a relatively small number of options, focusing mainly on the use of bone marrow-derived cells. Rapid clinical translation resulted in a number of small clinical trials that do not have sufficient power to address the therapeutic potential of the new approach. Moreover, full exploitation has been hindered so far by the absence of a solid theoretical framework and inadequate development plans. This article reviews the current knowledge on cell therapy and proposes a model theory for interpretation of experimental and clinical outcomes from a pharmacological perspective. Eventually, with an increased association between cell therapy and traditional pharmacotherapy, we will soon need to adopt a unified theory for understanding how the two practices additively interact for a patient's benefit.

Figure 1

Mechanisms of stem/progenitor cell action. Stem/progenitor cell, acting as a drug, incorporates into the niche or reconstitutes resident pool of cardiac stem cells (A). Stem/progenitor cell, acting as a pro-drug, is bioactivated by transdifferentiation (B). Stem/progenitor cell, acting as metabolite-releasing agent, release paracrine factors in controlled way – depot form (C). Stem/progenitor cell, acting as an indirect releasing agent, stimulate host cells to release paracrine factors, microRNAs, microvesicles and exosomes (D).

Figure 2

Synchronization of stem cell therapy and myocardial infarction is required to obtain significant improvement of heart function. The following variables must be optimized: cell type, route of administration, time interval between myocardial infarction and administration of cells, injection velocity and pressure, needle diameter, single or multiple injections, site of administration (border-zone/necrotic myocardium), injection into beating or arrested heart, application during reperfusion or occlusion, preconditioning effect, injectate volume and cell concentration.

Figure 3

Retention of stem/progenitor cells after intramyocardial (A) and intravascular – intracoronary and i.v – (B) administration. The wash-out of cells through the injection tract and/or impaired vascular system is proposed to be responsible for early mechanical loss. Stem/progenitor cell permeation depends on the chemoattractants concentration gradient, the number of cells having contact with infarct-related artery wall (exchange surface), cell concentration and coronary blood flow.