Exosomes Secreted by the Cocultures of Normal and Oxygen–Glucose-Deprived Stem Cells Improve Post-stroke Outcome
Emerging stroke literature suggests that treatment of experimentally induced stroke with stem cells offered post-stroke neuroprotection via exosomes produced by these cells. Treatment with exosomes has great potential to overcome the limitations associated with cell-based therapies. However, in our preliminary studies, we noticed that the exosomes released from human umbilical cord blood-derived mesenchymal stem cells (MSCs) under standard culture conditions did not improve the post-stroke neurological outcome. Because of this apparent discrepancy, we hypothesized that exosome characteristics vary with the conditions of their production. Specifically, we suggest that the exosomes produced from the cocultures of regular and oxygen–glucose-deprived (OGD) MSCs in vitro would represent the exosomes produced from MSCs that are exposed to ischemic brain cells in vivo, and offer similar therapeutic benefits that the cell treatment would provide. We tested the efficacy of therapy with exosomes secreted from human umbilical cord blood (HUCB)-derived MSCs under in vitro hypoxic conditions on post-stroke brain damage and neurological outcome in a rat model of transient focal cerebral ischemia. We performed the TTC staining procedure as well as the neurological tests including the modified neurological severity scores (mNSS), the modified adhesive removal (sticky-tape), and the beam walking tests before ischemia and at regular intervals until 7 days reperfusion. Treatment with exosomes obtained from the cocultures of normal and OGD-induced MSCs reduced the infarct size and ipsilateral hemisphere swelling, preserved the neurological function, and facilitated the recovery of stroke-induced rats. Based on the results, we conclude that the treatment with exosomes secreted from MSCs at appropriate experimental conditions attenuates the post-stroke brain damage and improves the neurological outcome.
KeywordsStem cells Exosomes Ischemia Reperfusion Brain damage Neurological recovery
We thank the William E. McElroy Charitable Foundation, the OSF HealthCare Illinois Neurological Institute, and the National Institutes of Health for the financial assistance. We thank Christina Constantinidou for assistance in manuscript format and review.
KKV conceived and designed the study. KKV, KRN, IV and AM performed the experiments and collected the data. KKV and KRN analyzed the data. KKV wrote the paper. JDK, DMP, DZW, and AK reviewed and edited the manuscript. All authors read and approved the manuscript. KRN and IV contributed equally to this work.
This work was supported by Grants from the William E. McElroy Charitable Foundation, the OSF HealthCare Illinois Neurological Institute, and the NIH Grant 1R01NS102573-01A1 to KKV. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.
Compliance with Ethical Standards
Conflicts of interest
The authors declare that they have no competing interests.
The Institutional Animal Care and Use Committee (IACUC) of the University of Illinois College of Medicine at Peoria approved all surgical interventions and post-operative animal care. All the animal experiments conducted were in accordance with the approved animal protocol and the IACUC guidelines.
Not applicable to this study.
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