Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition

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

Abstract

Disruption of blood-brain barrier (BBB), formed mainly by human brain microvascular endothelial cells (HBMECs), constitutes the major cause of mortality following ischaemic stroke. This study investigates whether OECs (outgrowth endothelial cells) can restore BBB integrity and function following ischaemic damage, and how inhibition of NOX2, a main source of vascular oxidative stress, affects the characteristics of BBB established with OECs and HBMECs in ischaemic settings. In vitro models of human BBB were constructed by co-culture of pericytes and astrocytes with either OECs or HBMECs before exposure to oxygen-glucose deprivation (OGD) alone or followed by reperfusion (OGD+R) in the absence or presence of NOX2 inhibitor, gp91ds-tat. The function and integrity of BBB were assessed by measurements of paracellular flux of sodium fluorescein (NaF) and transendothelial electrical resistance (TEER), respectively. Treatment with OECs during OGD+R effectively restored BBB integrity and function. Compared to HBMECs, OECs possessed lower NADPH oxidase activity, superoxide anion levels, and had greater total antioxidant capacity during OGD and OGD+R. Inhibition of NADPH oxidase during OGD and OGD+R restored the integrity and function of BBB established by HBMECs. This was evidenced by reductions in NADPH oxidase activity and superoxide anion levels. In contrast, treatment with gp91ds-tat aggravated ischaemic injury-induced BBB damage constructed by OECs. In conclusion, OECs are more resistant to ischaemic conditions and can effectively repair cerebral barrier following ischaemic damage. Suppression of oxidative stress through specific targeting of NOX2 requires close attention while using OECs as therapeutics.

Citation

Alwjwaj, M., Kadir, R. R. A., & Bayraktutan, U. (2022). Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition. European Journal of Neuroscience, 55(6), 1658-1670. https://doi.org/10.1111/ejn.15627

• Journal Article Type: Article
• Acceptance Date: Feb 15, 2022
• Online Publication Date: Feb 18, 2022
• Publication Date: Mar 1, 2022
• Deposit Date: Feb 19, 2022
• Publicly Available Date: Feb 19, 2023
• Journal: European Journal of Neuroscience
• Print ISSN: 0953-816X
• Electronic ISSN: 1460-9568
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 55
• Issue: 6
• Pages: 1658-1670
• DOI: https://doi.org/10.1111/ejn.15627
• Public URL: https://nottingham-repository.worktribe.com/output/7477546
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1111/ejn.15627
• Additional Information: This is the peer reviewed version of the following article: Alwjwaj, M., Kadir, R. R. A., & Bayraktutan, U. (2022). Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition. European Journal of Neuroscience, which has been published in final form at https://doi.org/10.1111/ejn.15627. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited.