Stem Cell Therapy Modulates Molecular Cues of Vasogenic Edema Following Ischemic Stroke: Role of Sirtuin-1 in Regulating Aquaporin-4 Expression

Abstract

Background
Conventional post-stroke edema management strategies are limitedly successful as in multiple cases of hemorrhagic transformation is being reported. Clinically, acute-ischemic-stroke (AIS) intervention by endovascular mesenchymal stem cells (MSCs) have shown benefits by altering various signaling pathways. Our previous studies have reported that intra-arterial administration of 1*10⁵ MSCs (IA-MSCs) were beneficial in alleviating post-stroke edema by modulating PKCδ/MMP9/AQP4 axis and helpful in preserving the integrity of blood-brain-barrier (BBB). However, the role of mitochondrial dysfunction and ROS generation post-AIS cannot be overlooked in context to the alteration of the BBB integrity and edema formation through the activation of inflammatory pathways. The anti-inflammatory activity of IA-MSCs in stroke has been reported to be regulated by sirtuin-1 (SIRT-1). Hence, the relationship between SIRT-1 and AQP4 towards regulation of post-stroke edema needs to be further explored. Therefore, the present study deciphers the molecular events towards AQP4 upregulation, mitochondrial dysfunction and BBB disruption in context to the modulation of SIRT-1/PKCδ/NFκB loop by IA-MSCs administration.

Methods
Ovariectomized SD rats were subjected to focal ischemia. SIRT-1 activator, SIRT-1 inhibitor, NFkB inhibitor and IA-MSCs were administered at optimized dose. At 24 h of reperfusion, behavioral tests were performed, and brains were harvested following euthanasia for molecular studies.

Results
IA-MSCs downregulated AQP4, PKCδ and NFkB expression, and upregulated SIRT-1 expression. SIRT-1 upregulation renders mitochondrial protection via reduction of oxidative stress resulting in BBB protection.

Conclusion
IA-MSCs can modulate SIRT-1 mediated AQP4 expression via mitochondrial ROS reduction and modification of NFkB transcriptional regulation.

Graphical Abstract

Full text

Stem Cell Reviews and Reports (2025) 21:797–815
https://doi.org/10.1007/s12015-025-10846-3
Introduction
Aquaporins (AQP), the gatekeeper of brain water homeosta-
sis are important mediators of cerebral edema [1]. Among
13 AQPs, AQP4 is most important channel as it is vastly
present in the brain astrocytes and plays crucial role in post-
stroke edema formation [1]. Ischemic stroke is a cerebro-
vascular event that results from a sudden decrease in brain
blood ow, leading to neuronal dysfunction and death [2].
The current FDA approved stroke therapies have a narrow
time window that limits their optimum eectiveness [3].
Therefore, there is requirement of adjunctive therapy that
Pallab Bhattacharya
pallab.bhu@gmail.com;
pallab.bhattacharya@niperahm.res.in
1 Department of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research
(NIPER), Ahmedabad, Gandhinagar, Gujarat, India
2 Department of Life Science and Bioinformatics, Cellular
and Molecular Neurobiology Laboratory, Assam University,
Silchar, Assam, India
3 Department of Neurology and Neurosurgery, University of
Miami Miller School of Medicine, Miami, FL, USA
Summary
Background Conventional post-stroke edema management strategies are limitedly successful as in multiple cases of hemor-
rhagic transformation is being reported. Clinically, acute-ischemic-stroke (AIS) intervention by endovascular mesenchymal
stem cells (MSCs) have shown benets by altering various signaling pathways. Our previous studies have reported that intra-
arterial administration of 1*105 MSCs (IA-MSCs) were benecial in alleviating post-stroke edema by modulating PKCδ/
MMP9/AQP4 axis and helpful in preserving the integrity of blood-brain-barrier (BBB). However, the role of mitochondrial
dysfunction and ROS generation post-AIS cannot be overlooked in context to the alteration of the BBB integrity and edema
formation through the activation of inammatory pathways. The anti-inammatory activity of IA-MSCs in stroke has been
reported to be regulated by sirtuin-1 (SIRT-1). Hence, the relationship between SIRT-1 and AQP4 towards regulation of
post-stroke edema needs to be further explored. Therefore, the present study deciphers the molecular events towards AQP4
upregulation, mitochondrial dysfunction and BBB disruption in context to the modulation of SIRT-1/PKCδ/NFκB loop by
IA-MSCs administration.
Methods Ovariectomized SD rats were subjected to focal ischemia. SIRT-1 activator, SIRT-1 inhibitor, NFkB inhibitor and
IA-MSCs were administered at optimized dose. At 24 h of reperfusion, behavioral tests were performed, and brains were
harvested following euthanasia for molecular studies.
Results IA-MSCs downregulated AQP4, PKCδ and NFkB expression, and upregulated SIRT-1 expression. SIRT-1 upregu-
lation renders mitochondrial protection via reduction of oxidative stress resulting in BBB protection.
Conclusion IA-MSCs can modulate SIRT-1 mediated AQP4 expression via mitochondrial ROS reduction and modication
of NFkB transcriptional regulation.
Keywords Post-stroke Edema · IA Mesenchymal stem cell · Mitochondrial ROS · Aquaporin 4 · Sirtuin 1 · Blood
Brain Barrier
Accepted: 20 January 2025 / Published online: 31 January 2025
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2025
Stem Cell Therapy Modulates Molecular Cues of Vasogenic Edema
Following Ischemic Stroke: Role of Sirtuin-1 in Regulating Aquaporin-4
Expression
AishikaDatta1· BijoyaniGhosh1· AnirbanBarik1· GautamKarmarkar1· DeepaneetaSarmah1· AnupomBorah2·
ShailendraSaraf1· Dileep R.Yavagal3· PallabBhattacharya1
1 3
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