Challenging the great vascular wall: Can we envision a simple yet comprehensive therapy for stroke?

Abstract

Stroke is a leading cause of death in adult life, closely behind ischemic heart disease, and causes a significant and abiding socioeconomic burden. However, current therapies are not able to ensure full neurologic and/or sequelae-free recovery to all stroke survivors. We believe treatment efficacy and patient rehabilitation could be enhanced significantly by targeting bloodbrain barrier (BBB) deregulation and inflammation-induced barrier loss that occurs after stroke. In this pathological context, bone marrow-derived endothelial progenitor cells (EPC) enter the bloodstream towards the lesion site, but their insufficient numbers and impaired angiogenic ability compromise neurovascular regeneration. In this context, cell-based therapies have become increasingly appealing since treating patients with large numbers of mesenchymal or hematopoietic stem/progenitor cells alone may boost repair. However, this approach could be met with several challenges in terms of logistics and cost; hence, the development of a drug delivery system suitable for intravenous administration and functionalized for selective uptake by circulating EPC could enhance their restorative potential without perceived complications. The ability to encapsulate proangiogenic and anti-inflammatory agents, such as retinoic acid, and to safely and easily deliver them systemically may open new therapeutic perspectives for the treatment of cerebrovascular disorders.

Anti-Inflammatory Strategy for M2 Microglial Polarization Using Retinoic Acid-Loaded Nanoparticles

“…In that sense, a functionalized formulation (targeting endothelial cells, which can internalize RA-NP) could possibly become a more efficient approach [ 20 , 45 ]. A BBB-targeted therapy would restrain vascular activation and prevent glia induced-barrier loss [ 46 ].…”

Endothelial progenitor cells: Potential novel therapeutics for ischaemic stroke

“…Intriguingly, in most clinical studies probing the safety and efficacy of autologous stem cells in ischaemic stroke, bone marrow-derived or adipose tissue-derived mesenchymal cells have been used. While the remaining few studies focused on intracerebral or intra-arterial application of peripheral blood-derived or umbilical cord blood-derived haematopoietic stem cells, only 6 studies registered at the ClinicalTrials.gov (Table 1) have examined or continue to examine the therapeutic capacity or diagnostic and prognostic value of EPCs in ischaemic stroke patients [53,54].…”

Endothelial Progenitor Cells for Ischemic Stroke: Update on Basic Research and Application

“…Most clinical trials are focusing on bone marrow- or adipose tissue-derived mesenchymal cell transplantation (NCT02378974; NCT01091701; NCT01461720; NCT01678534; NCT01716481; NCT01922908; NCT01297413; NCT00875654; NCT02580019;NCT01714167; NCT02580019; NCT01714167; NCT02580019; and NCT02564328). The remaining studies use peripheral blood- or umbilical cord blood-derived hematopoietic stem cells intracerebrally or infused into the middle cerebral artery of patients (NCT01518231; NCT01249287; NCT00761982; NCT01438593; and NCT00950521) [ 108 ]. In this review, we have also queried clinical trials of EPC application in ischemic stroke in ClinicalTrials.gov ( Table 1 ), which have no available results reported.…”

“…It can also protect its carriers and may be released in a controlled manner [ 127 – 130 ]. Nanoparticles can be implanted in molecules, such as VEGF, FGF-2, transforming growth factor- β (TGF- β ), G-CSF, and PDGF [ 108 ], that promote EPC function and coated the surface with the amino acid sequence LQNAPRS, which has recently been shown to recognize CD133 [ 131 ] and anti-CD34 antibodies that are used to recognize EPC [ 132 ], which is a type of nanoparticle that contributes to EPC survival and promote angiogenesis. Experiments were carried out using a synthetic pH-sensitive polymer (urethane spherical sulfamethazine) to load SDF-1 α and release it in the local acidic environment of the cerebral infarction [ 133 ]; other experiments used computer to redesign SDF peptide analogues, which would more effectively induce EPC migration [ 134 ] and enhance neurogenesis and angiogenesis.…”