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

Kadir, Rais Reskiawan A.; Alwjwaj, Mansour; Rakkar, Kamini; Othman, Othman Ahmad; Sprigg, Nikola; Bath, Philip M.; Bayraktutan, Ulvi


Rais Reskiawan A. Kadir

Mansour Alwjwaj

Kamini Rakkar

Othman Ahmad Othman

Professor of Stroke Medicine

Philip M. Bath


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 in vitro 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.


Kadir, R. R. A., Alwjwaj, M., Rakkar, K., Othman, O. A., Sprigg, N., Bath, P. M., & Bayraktutan, U. (2022). Outgrowth Endothelial Cell Conditioned Medium Negates TNF-?-Evoked Cerebral Barrier Damage: A Reverse Translational Research to Explore Mechanisms. Stem Cell Reviews and Reports,

Journal Article Type Article
Acceptance Date Jul 28, 2022
Online Publication Date Sep 2, 2022
Publication Date Sep 2, 2022
Deposit Date Sep 3, 2022
Publicly Available Date Sep 6, 2022
Journal Stem Cell Reviews and Reports
Print ISSN 1550-8943
Electronic ISSN 2629-3277
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Public URL
Publisher URL


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