The secretome of endothelial progenitor cells: a potential therapeutic strategy for ischemic stroke

Abstract

Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window (4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells (EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity.

Keywords: antioxidants; cell-based therapy; cell-free therapy; endothelial progenitor cells; inflammatory cytokines; regenerative medicine; secretome; stroke; vasodegeneration; vasorepair.

Figure 1

Schematic representation of neurovascular unit.

Figure 2

Schematic representation of the effect of ischemic stroke on neurovascular unit. A sudden disruption in cerebral blood flow and ensuing decreases in oxygen and energy supply triggers oxidative stress and compromises the integrities of tight junctions and blood-brain barrier (BBB). Overproduction of inflammatory cytokines and excitotoxicity further damage neuronal loss and BBB damage thereby leading to formation of cerebral edemas. ATP: Adenosine triphosphate; ECs: endothelial cells; IL: interleukin; ROS: reactive oxygen species; TNFα: tumor necrosis factor α.

Figure 3

Possible mechanism of action of EPC secretome on restoration of neurovascular unit during or after an ischemic stroke. EPC-secretome containing many biologically active substances such as growth factors, cathepsins, cytokines and chemokines may evoke endogenous regeneration and neovascularization by activating resident endothelial cells, inhibiting oxidative stress and concomitantly inducing angiogenesis and neurogenesis. EC: Endothelial cell; EPC: endothelial progenitor cell.