Introduction: Our previous studies have demonstrated that transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after experimental intracerebral hemorrhage (ICH). Exosomes are membrane-contained vesicles with cytoplasmic components and cargo proteins which are released into the surrounding interstitial fluid. Their contents are protected from degradative extracellular enzymes. In this study we tested a novel hypothesis that administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling and neurogenesis in rats after ICH.
Methods: Male Wistar rats were subjected to ICH followed 24 hours later by tail vein injection of 100 µg protein of exosomes derived from MSCs or an equal volume of vehicle phosphate-buffered saline (n = 8/group). To evaluate cognitive and sensorimotor functional recovery, the modified neurological severity score (mNSS), the modified Morris water maze test, and a social odor-based novelty recognition test were performed after ICH. Animals were sacrificed 28 days after ICH. Immunohistochemical analysis was performed for measurements of lesion volume and neurovascular remodeling. Statistical analysis was performed using ANOVA.
Results: Compared with saline-treated control rats, exosome-treated ICH rats showed significant improvement in spatial learning at 24-28 days measured by the Morris water maze test (p<0.05). There also was significant improvement in the mNSS and sensorimotor functional recovery, measured by a social odor-based test (both with p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the hematoma boundary zone (p<0.05). Treated animals also had a significantly increased number of neuroblasts and mature neurons in the subventricular zone (p<0.05), although the total lesion volume in the treated animals was similar to the control animals.
Conclusions: MSC-generated exosomes effectively improve neurological outcome after experimental ICH, at least in part, by promoting endogenous angiogenesis and neurogenesis. MSC-generated cell free exosomes may be a novel therapy to improve recovery after ICH.
Patient Care: we are working toward treatment of ICH with neurorestorative compounds to improve clinical outcome.
Learning Objectives: By the conclusion of this session, participants should be able to describe the histological findings in the experimental model of ICH and the importance of cellular remodeling after treatment, specifically with with MSC derived exosomes.
References: Seyfried D, Ding J, Han Y, Li Y, Chen J, Chopp M. Effects of intravenous administration of human bone marrow stromal cells after intracerebral hemorrhage in rats. J Neurosurg. 2006;104(2):313-8. doi: 10.3171/jns.2006.104.2.313. PubMed PMID: 16509507.