Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke.
Transplantation of mesenchymal stem cells (MSCs) was reported to improve functional outcomes in a rat model of ischemic stroke, and subsequent studies suggest that MSC-derived microvesicles (MVs) can replace the beneficial effects of MSCs. Here, we evaluated three different MSC-derived MVs, including MVs from untreated MSCs (MSC-MVs), MVs from MSCs treated with normal rat brain extract (NBE-MSC-MVs), and MVs from MSCs treated with stroke-injured rat brain extract (SBE-MSC-MVs), and tested their effects on ischemic brain injury induced by permanent middle cerebral artery occlusion (pMCAO) in rats. NBE-MSC-MVs and SBE-MSC-MVs had significantly greater efficacy than MSC-MVs for ameliorating ischemic brain injury with improved functional recovery. We found similar profiles of key signalling proteins in NBE-MSC-MVs and SBE-MSC-MVs, which account for their similar therapeutic efficacies. Immunohistochemical analyses suggest that brain-extract-treated MSC-MVs reduce inflammation, enhance angiogenesis, and increase endogenous neurogenesis in the rat brain. We performed mass spectrometry proteomic analyses and found that the total proteomes of brain-extract-treated MSC-MVs are highly enriched for known vesicular proteins. Notably, MSC-MV proteins upregulated by brain extracts tend to be modular for tissue repair pathways. We suggest that MSC-MV proteins stimulated by the brain microenvironment are paracrine effectors that enhance MSC therapy for stroke injury.
Institute for BioMedical Convergence, Catholic Kwandong University-International St. Mary's Hospital, Incheon 22711, Republic of Korea.
Ji Yong
JY
Lee
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Eiru
E
Kim
Institute for BioMedical Convergence, Catholic Kwandong University-International St. Mary's Hospital, Incheon 22711, Republic of Korea.
Seong-Mi
SM
Choi
Department of Physiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Dong-Wook
DW
Kim
Department of Applied Chemistry, College of Applied Science, Kyung Hee University, Yongin, 17104, Republic of Korea.
Kwang Pyo
KP
Kim
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Insuk
I
Lee
Institute for BioMedical Convergence, Catholic Kwandong University-International St. Mary's Hospital, Incheon 22711, Republic of Korea.|Department of Biomedical Sciences, Catholic Kwandong University College of Medicine, Gangneung-si, Gangwon-do 25601, Republic of Korea.
Han-Soo
HS
Kim
D000818:Animals; D001921:Brain; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D055252:Cell-Derived Microparticles; D045424:Complex Mixtures / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D059630:Mesenchymal Stem Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020521:Stroke / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
D045424:Complex Mixtures