Factors Secreted by Endothelial Progenitor Cells Enhance Neurorepair Responses after Cerebral Ischemia in Mice

Abstract

Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM) obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI) was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky’s staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke.

NSI‐189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats

“…Similar reports have demonstrated cross‐talk between secreted factors (e.g., apoptosis, inflammation, oxidative stress) (; Brill et al, 2009; Chapman et al, 2015; Lu, Jones, Snyder, & Tuszynski, 2003; Zhang et al, 2015) and neurogenesis following brain insults, including stroke (Kernie and Parent, 2010; Yamashita et al, 2006). We (Hara et al, 2007; Morimoto et al, 2011; Tajiri et al, 2013), and others, have shown the important contribution of neurogenic factors in stroke brain remodeling (Jablonska et al, 2016; Rosell et al, 2013; Seo et al, 2014; Venna, Xu, Doran, Patrizz, & McCullough, 2014). Altogether, these results allude to host neurogenesis and its secreted neurogenic factors as key therapeutic targets of NSI‐189 in affording behavioral and neurostructural benefits in stroke.…”

Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway

“…According to some studies, VEGF overexpression reduces infarct volume and improves post-ischemic motor function, which may contribute to brain recovery and repair [8] . Furthermore, vascular endothelial cells secrete VEGF to promote the proliferation of NSCs [9] . BDNF is a member of the nerve growth factor family and is released after hypoxia or ischemia to protect the brain from injury.…”

“…Sample and standard dilutions were made with the experimental media, and the results are expressed as the means±SD [9] .…”

Impaired Vascular Remodeling after Endothelial Progenitor Cell Transplantation in MMP9-Deficient Mice Suffering Cortical Cerebral Ischemia

“…2 Both types of EPCs have been demonstrated to increase brain angiogenesis in animal models of cerebral ischemia. [3][4][5] The degradation and remodeling of the vascular basal membrane is required to allow endothelial cells to migrate, and matrix metalloproteinases (MMPs) have key roles in the initial steps of angio-vasculogenesis. Specifically, MMP9 has been shown to be essential for the invasion of endothelial cells and capillary branching, and in vitro studies have indicated that its absence impairs the angiogenic abilities of the EPCs.…”