95% of researchers rate our articles as excellent or good
Learn more about the work of our research integrity team to safeguard the quality of each article we publish.
Find out more
ORIGINAL RESEARCH article
Front. Neurol.
Sec. Experimental Therapeutics
Volume 16 - 2025 | doi: 10.3389/fneur.2025.1543133
Effects of low-intensity pulsed focal ultrasound-mediated delivery of endothelial progenitor-derived exosomes in tMCAo stroke
Provisionally accepted
Ahmet Alptekin 1
Mohammad B Khan 1
Mahrima Parvin 1 Hasanul Chowdhury 1 Sawaiz Kashif 1 Fowzia Akter Selina 1 Anika Bushra 1 Justin Kelleher 1 Santu Ghosh 1 Dylan Williams 1 Emily Blumling 1 Roxan Ara 1
Asamoah Bosomtwi 1
Joseph A Frank 2
Krishnan M Dhandapani 1
Ali Syed Arbab 1*- 1 Augusta University, Augusta, United States
- 2 National Institutes of Health (NIH), Bethesda, Maryland, United States
Abstract:Exosomes from different sources have been used for therapeutic purposes to target stroke and other disorders. However, exosomes from endothelial progenitor cells (EPCs) have not been tested in any stroke model, and in vivo bio-distribution study is lacking. Targeted delivery of IV-administered exosomes has been a significant challenge. Delivery of exosomes to the brain is a daunting task, and a blood-brain barrier (BBB)-penetrable peptide is being considered. However, the next step in practical treatment will be delivering naïve (unmodified) exosomes to the stroke site without destroying host tissues or disrupting BBB, or the membranes of the delivery vehicles. Low-intensity-pulsed focused ultrasound (LIPFUS) is approved for clinical use in the musculoskeletal, transcranial brain, and physiotherapy clinics. The objectives of the proposed studies were to determine whether LIPFUS-mediated increased delivery of EPC-derived exosomes enhances stroke recovery and functional improvement in mice with transient middle cerebral artery occlusion (tMCAo) stroke. To enhance exosome delivery to the stroke area, we utilized LIPFUS. We evaluated stroke volume using MRI at different time points and conducted behavioral studies parallel to MRI to determine recovery. Ultimately, we studied brain tissue using immunohistochemistry to assess the extent of stroke and tissue regeneration. In vivo, imaging showed a higher accumulation of EPC exosomes following LIPFUS without any damage to the underlying brain tissues, increased leakage of albumin, or accumulation of CD45+ cells. Groups of mice (14-16 months old) were treated with Vehicle (PBS), LIPFUS only, EPC-exosomes only, and LIPFUS+EPC-exosomes. LIPFUS + EPC exosomes groups showed a significantly decreased stroke volume on day 7, decreased FluoroJade+ cells, and significantly higher numbers of neovascularization in and around the stroke areas compared to that of other groups.
Keywords: ischemic stroke, Exosomes, Low-intensity-pulsed focused ultrasound (LIPFUS), magnetic resonance imaging (MRI), Single photon emission computed tomography (SPECT)
Received: 10 Dec 2024; Accepted: 24 Mar 2025.
Copyright: © 2025 Alptekin, Khan, Parvin, Chowdhury, Kashif, Selina, Bushra, Kelleher, Ghosh, Williams, Blumling, Ara, Bosomtwi, Frank, Dhandapani and Arbab. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ali Syed Arbab, Augusta University, Augusta, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.