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.

Treatment with outgrowth endothelial cells protects cerebral barrier against ischemic injury

“…It controls the exchange of molecules between systemic circulation and the brain parenchyma to maintain the cerebral physiological function [22]. Since BBB damage constitutes the main cause of death and neurological deterioration in the first week of ischaemic stroke, restoration of this distinctive barrier may be a very effective therapeutic strategy to mitigate stroke-related damage [23,24]. Re-endothelialisation of dead or dying cerebral vasculature not only relies on the lateral migration and proliferation of resident brain endothelial cells but also on the bioavailability of functional OECs, which can promote endothelial repair directly (through differentiation into endothelial cells) or indirectly (by releasing various paracrine elements) [9].…”

Therapeutic hypothermia augments the restorative effects of PKC-β and Nox2 inhibition on an in vitro model of human blood–brain barrier

“…Despite a large number of agents have, over the years, been shown to protect cerebrovascular integrity and function in experimental settings, the subsequent clinical trials performed with the same agents failed to replicate these favourable effects. One of the main drawbacks regarding translational stroke research is that the majority of the agents used in the above-mentioned clinical trials have focused on a single pathway pertaining to either recanalisation of vessels or excitotoxicity to reduce neuronal death, while many other processes are involved spatially and temporally in the pathophysiology of stroke (Alwjwaj et al 2021 ; Loach and Bayraktutan 2016 ). In this context, therapeutic hypothermia capable of targeting multiple pathways, notably oxidative stress, inflammatory responses, metabolic disruption and cell death signals may be a potentially effective procedure (Loach and Bayraktutan 2017 ).…”

“…Ischaemic stroke stemming from an interference with blood supply leading to or within the brain continues to be one of the main causes of mortality and morbidity worldwide. Disruption of the blood–brain barrier (BBB) and ensuing vasogenic oedema constitute the main causes of neurological impairment during the acute phase of ischaemic strokes (Alwjwaj et al 2021 ; Jiang et al 2018 ). Prolonged exposure to hyperglycaemia in patients with diabetes mellitus (DM) amplifies the extent of stroke-mediated BBB disruption through thickening of the capillary basement membrane and increases in oxidative stress, neuronal and endothelial cell apoptosis (Venkat et al 2017 ).…”

Endothelial Progenitor Cells in Moyamoya Disease: Current Situation and Controversial Issues

“…Since the first description of EPCs by Asahara et al in 1997 21 , there have been a lot of studies on EPCs in various diseases, such as hypertension 63 , cardiovascular disease 64 , and cerebrovascular diseases 26 . Especially in cerebral ischemia stroke, EPCs-based cell therapy is now considered an important new therapeutic approach 65 . EPCs have also attracted attention in the pathogenetic study of MMD.…”