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Embryonic Stem Cell-Derived Endothelial Cells for Treatment of Hindlimb Ischemia
Published on: January 23, 2009
Development of endothelial-targeted CD39 as a therapy for ischemic stroke
Natasha Ting Lee1, Ioanna Savvidou2, Carly Selan2
1Australian Centre for Blood Diseases, School of Translational Medicine, Monash University, Alfred Hospital, Melbourne, Victoria, Australia; Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia; Monash Biomedical Imaging, Monash University, Clayton, Victoria, Australia.
Targeted CD39 therapy effectively salvaged brain tissue in ischemic stroke models, reducing infarct size and improving outcomes. This novel approach shows promise as a standalone treatment or in combination with thrombolytics like tissue plasminogen activator (tPA).
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Ischemic stroke involves a core necrotic lesion and a surrounding penumbra of dying cells.
- Microglial activation and thromboinflammation contribute to stroke progression and vascular disruption.
- The ecto-enzyme CD39 regulates extracellular adenosine triphosphate, offering antithrombotic and anti-inflammatory benefits.
Purpose of the Study:
- To evaluate the efficacy of anti-VCAM-CD39 as a therapeutic agent for ischemic stroke.
- To determine if targeting CD39 to activated endothelium in the penumbra improves stroke outcomes.
Main Methods:
- Developed anti-VCAM-CD39 to target CD39 to vascular cell adhesion molecule-1 (VCAM-1) on activated endothelial cells.
- Utilized a mouse model of middle cerebral artery occlusion (MCAO) for 30 minutes, with treatment administered 3 hours post-MCAO.
- Compared anti-VCAM-CD39 to control agents (saline, nontargeted CD39, anti-VCAM-inactive CD39) and assessed outcomes at 24 hours.
Main Results:
- Anti-VCAM-CD39 significantly reduced neurological deficits and infarct volume, confirmed by MRI.
- Treatment increased cerebrovascular perfusion, restored blood-brain barrier integrity, and decreased microglial activation.
- Combination therapy with tissue plasminogen activator (tPA) further reduced infarct size and blood-brain barrier permeability without increasing hemorrhage.
Conclusions:
- Anti-VCAM-CD39 demonstrates potential as a novel stroke therapy, even when administered 3 hours after ischemia.
- Targeting CD39 to endothelial cells offers a unique therapeutic strategy for salvaging the penumbra.
- Synergistic effects observed with thrombolytic therapy suggest improved stroke outcomes with combination treatment.
