Treatment with outgrowth endothelial cells protects cerebral barrier against ischemic injury

Kadir, Rais Reskiawan A.; Alwjwaj, Mansour; Bayraktutan, Ulvi

doi:10.1016/j.jcyt.2021.11.005

Cited by 17 publications

(10 citation statements)

References 49 publications

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“…EPCs/OECs can differentiate into mature ECs and release a wide range of trophic factors to maintain BBB integrity in all (physio)pathological settings [ 13 ]. Indeed, recovery of BBB and neurological functions in stroke rats treated with OECs 24–48 h after middle cerebral artery occlusion (MCAo) confirmed the ability of these cells to engraft into brain capillaries and serve as therapeutics [ 14 , 15 ]. However, replicative senescence of OECs during large scale ex vivo expansion and elevated risk of emboli formation and immune reaction associated with cell-based therapies have thus far hampered the widespread use of these particular cells in clinical practice [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Outgrowth Endothelial Cell Conditioned Medium Negates TNF-α-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms

Kadir

Alwjwaj

Rakkar

et al. 2022

Stem Cell Rev and Rep

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Improved understanding of the key mechanisms underlying cerebral ischemic injury is essential for the discovery of efficacious novel therapeutics for stroke. Through detailed analysis of plasma samples obtained from a large number of healthy volunteers (n = 90) and ischemic stroke patients (n = 81), the current study found significant elevations in the levels of TNF-α at baseline (within the first 48 h of stroke) and on days 7, 30, 90 after ischaemic stroke. It then assessed the impact of this inflammatory cytokine on an invitro model of human blood–brain barrier (BBB) and revealed dramatic impairments in both barrier integrity and function, the main cause of early death after an ischemic stroke. Co-treatment of BBB models in similar experiments with outgrowth endothelial cell-derived conditioned media (OEC-CM) negated the deleterious effects of TNF-α on BBB. Effective suppression of anti-angiogenic factor endostatin, stress fiber formation, oxidative stress, and apoptosis along with concomitant improvements in extracellular matrix adhesive and tubulogenic properties of brain microvascular endothelial cells and OECs played an important role in OEC-CM-mediated benefits. Significant increases in pro-angiogenic endothelin-1 and monocyte chemoattractant protein-1 in OEC-CM compared to the secretomes of OEC and HBMEC, detected by proteome profiling assay, accentuate the beneficial effects of OEC-CM. In conclusion, this reverse translational study identifies TNF-α as an important mediator of post-ischemic cerebral barrier damage and proposes OEC-CM as a potential vasculoprotective therapeutic strategy by demonstrating its ability to regulate a wide range of mechanisms associated with BBB function. Clinical trial registration NCT02980354. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Outgrowth Endothelial Cell Conditioned Medium Negates TNF-α-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms

Kadir

Alwjwaj

Rakkar

et al. 2022

Stem Cell Rev and Rep

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“…Substantial decreases reported in the number of circulating EPCs expressing markers specifically for stemness and immaturity in healthy individuals over 65 years of age versus those between 18 and 64 years confirm the influence of ageing on distinct EPC subtypes 10 . In light of these and further findings implying the value of circulating EPCs for endothelial repair 6 , 11 , 17 and as potential prognostic biomarkers 18 , the present study hypothesised that changes in circulating numbers of certain EPC subtypes, defined as cells co-expressing a variety of markers for stemness (CD34 +), immaturity (CD133 +) and endothelial cell maturity (KDR +), may explain the differences reported in the severity and/or outcome of ischaemic stroke in older patients. Observation of a significant correlation in the current study between higher CD34 + KDR + and CD133 + KDR + numbers during the acute phase of stroke and better neurological and functional outcome on D90 post-stroke corroborate this hypothesis and attribute a key role to these particular EPC subtypes in neurovascular repair 19 , 20 .…”

Section: Discussionmentioning

confidence: 80%

“…The endothelium is important in preserving vascular homeostasis 4 , 5 . Endothelial progenitor cells (EPCs), released from bone marrow, play an instrumental role in maintaining appropriate endothelial function by re-endothelialisation of cerebral blood vessels after IS 6 , 7 . Similar to embryonic angioblasts, EPCs are equipped with an inherent capacity to proliferate, migrate and differentiate.…”

Section: Introductionmentioning

confidence: 99%

Analysis of endothelial progenitor cell subtypes as clinical biomarkers for elderly patients with ischaemic stroke

Kadir,

Rakkar,

Othman

et al. 2023

Sci Rep

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Endothelial progenitor cells (EPCs), expressing markers for stemness (CD34), immaturity (CD133) and endothelial maturity (KDR), may determine the extent of post-stroke vascular repair. Given the prevalence of stroke in elderly, this study explored whether variations in plasmatic availability of certain EPC subtypes could predict the severity and outcome of disease in older patients. Blood samples were collected from eighty-one consented patients (≥ 65 years) at admission and days 7, 30 and 90 post-stroke. EPCs were counted with flow cytometry. Stroke severity and outcome were assessed using the National Institutes of Health Stroke Scale, Barthel Index and modified Rankin Scale. The levels of key elements known to affect EPC characteristics were measured by ELISA. Diminished total antioxidant capacity and CD34 + KDR + and CD133 + KDR + counts in early phases of stroke were associated with disease severity and worse functional outcome at day 90 post-stroke. Baseline levels of angiogenic agent PDGF-BB, but not VEGF, positively correlated with CD34 + KDR + numbers at day 90. Baseline LDL-cholesterol levels were inversely correlated with CD34 + KDR+, CD133 + KDR + and CD34 + CD133 + KDR + numbers at day 90. Close correlation between baseline CD34 + KDR + and CD133 + KDR + counts and the outcome of stroke proposes these particular EPC subtypes as potential prognostic markers for ischaemic stroke.

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“…Reconstructing the BBB is considered a promising treatment option for ischemic stroke. Kadir RRA et al [ 137 ] established an in vitro BBB model through cell co-culture and demonstrated that overgrown endothelial cells (OECs) can effectively migrate to the injured site and restore BBB integrity. OEC-based cell therapy can also reduce oxidative stress and apoptosis of cerebral microvascular endothelial cells after ischemic stroke injury.…”

Section: Blood-brain Barriermentioning

confidence: 99%

Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke

Gao,

Chen,

Cui

et al. 2023

Cell Biosci

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The blood-brain barrier (BBB) serves as a defensive line protecting the central nervous system, while also maintaining micro-environment homeostasis and inhibiting harmful materials from the peripheral blood. However, the BBB’s unique physiological functions and properties make drug delivery challenging for patients with central nervous system diseases. In this article, we briefly describe the cell structure basis and mechanism of action of the BBB, as well as related functional proteins involved. Additionally, we discuss the various mechanisms of BBB damage following the onset of an ischemic stroke, and lastly, we mention several therapeutic strategies accounting for impairment mechanisms. We hope to provide innovative ideas for drug delivery research via the BBB.

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Treatment with outgrowth endothelial cells protects cerebral barrier against ischemic injury

Cited by 17 publications

References 49 publications

Outgrowth Endothelial Cell Conditioned Medium Negates TNF-α-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms

Outgrowth Endothelial Cell Conditioned Medium Negates TNF-α-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms

Analysis of endothelial progenitor cell subtypes as clinical biomarkers for elderly patients with ischaemic stroke

Damage mechanism and therapy progress of the blood-brain barrier after ischemic stroke

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