Therapeutic revascularisation of ischaemic tissue: the opportunities and challenges for therapy using vascular stem/progenitor cells

Abstract

Ischaemia-related diseases such as peripheral artery disease and coronary heart disease constitute a major issue in medicine as they affect millions of individuals each year and represent a considerable economic burden to healthcare systems. If the underlying ischaemia is not sufficiently resolved it can lead to tissue damage, with subsequent cell death. Treating such diseases remains difficult and several strategies have been used to stimulate the growth of blood vessels and promote regeneration of ischaemic tissues, such as the use of recombinant proteins and gene therapy. Although these approaches remain promising, they have limitations and results from clinical trials using these methods have had limited success. Recently, there has been growing interest in the therapeutic potential of using a cell-based approach to treat vasodegenerative disorders. In vascular medicine, various stem cells and adult progenitors have been highlighted as having a vasoreparative role in ischaemic tissues. This review will examine the clinical potential of several stem and progenitor cells that may be utilised to regenerate defunct or damaged vasculature and restore blood flow to the ischaemic tissue. In particular, we focus on the therapeutic potential of endothelial progenitor cells as an exciting new option for the treatment of ischaemic diseases.

Figure 1

Schematic representing the role of stem and progenitor cells in vascular repair. Multiple stem and progenitor cells may contribute to vascular repair in vivo. Both embryonic stem cells (ESCs; blue) and induced pluripotent stem cells (iPSCs; orange) can be differentiated into vascular cells and may be utilised in vivo as endothelial cells with the potential to engraft into damaged or ischaemic host vasculature. Mesenchymal stem cells (MSCs; pink) have the potential to differentiate into mural cells such as pericytes and smooth muscle cells. This would be particularly useful in ischaemic tissue as mural cells are essential for stabilisation of newly formed vessels and communicate closely with endothelial cells through adherens junctions. The protein N-cadherin is depicted as pink diamonds. Multipotent adult progenitor cells (MAPCs purple) may also be differentiated into endothelial cells to aid vascular repair and reduce ischaemia. Early endothelial progenitor cells/myeloid angiogenic cells (eEPCs/MACs; red) play a paracrine role by secreting pro-angiogenic growth factors and cytokines (yellow triangles and blue squares) to stimulate vascular regeneration. Outgrowth endothelial cells (OECs; green) display a typical endothelial phenotype and have clinical potential for ischaemic disease as they home to ischaemic areas and directly integrate into denuded endothelium.