Cardiac regeneration: current therapies-future concepts

Abstract

Cardiovascular disease (CVD) continues to be one of the main causes of death in the western world. A high burden of disease and the high costs for the healthcare systems claim for novel therapeutic strategies besides current conventional medical care. One decade ago first clinical trials addressed stem cell based therapies as a potential alternative therapeutic strategy for myocardial regeneration and repair. Besides bone marrow derived stem cells (BMCs), adult stem cells from adipose or cardiac tissue have been used in current clinical studies with inconsistent results. Although outcomes in terms of safety and feasibility are generally encouraging, functional improvements were mostly disappointingly low and have failed to reach expectations. In the future, new concepts for myocardial regeneration, especially concerning recovery of cardiomyocyte loss, have to be developed. Transplantation of novel stem or progenitor cell populations with "true" regenerative potential, direct reprogramming of scar tissue into functional myocardium, tissue engineering or stimulation of endogenous cardiac repair by pharmacological agents are conceivable. This review summarizes current evidence of stem cell based regenerative therapies and discusses future strategies to improve functional outcomes.

Keywords: Myocardial infarction; regenerative medicine; reprogramming; stem cells; tissue engineering.

Figure 1

Regenerative therapies and cell sources currently administered in clinical trials. Current clinical trials use BMCs, ADRCs or CPCs to regenerate impaired myocardium after ischemic events. Alternatively cytokines like EPO or G-CSF are employed to mobilize resident progenitor cells from the bone marrow. BMCs, bone marrow cells; ADRCs, adipose-tissue derived regenerative cells; CPCs, cardiopoietic stem cells; CP-cocktail, cardiopoietic cocktail; CDCs, cardiosphere derived cells; G-CSF, granulocyte colony stimulating factor; EPO, erythropoietin.

Figure 2

Novel stem cell sources for cardiac regeneration. ESCs (Embryonic stem cells) and iPSCs (induced pluripotent stem cells) generated by reprogramming fibroblasts can be differentiated into cardiac lineages. Cardiac differentiation means the gradual maturation of pluripotent cells (ESCs, iPSCs) over several progenitor stages to functional adult cardiomyocytes. Another approach is to directly convert mature somatic cells like fibroblasts into other mature cell types like cardiomyocytes. It is also imaginable that fibroblasts can be driven to an intermediate stage between full pluripotency and total maturity: a cardiac progenitor stage that is already directed to a cardiac fate but still maintains the ability to proliferate and differentiate in endothelial cells, smooth muscle cells or cardiomyocytes.

Figure 3

Future concepts for regenerative therapies. Future therapies in terms of myocardial regeneration might be a consolidation of transplantation of cells with “true” regenerative potential, tissue engineering with various scaffolds and cell types, a stimulation of resident cell sources by cytokines or growth factors or a direct reprogramming of scar tissue by delivery of various transcription factors or miRNAs. ESCs, embryonic stem cells; iPSCs, induced pluripotent stem cells; NRG1, neuregulin 1; p38 MAP KI, p38 MAP kinase inhibitor; P, periostin; miRNA, micro RNA.