Reduced ischemic brain injury by partial rejuvenation of bone marrow cells in aged rats.
Circulating bone marrow-derived immature cells, including endothelial progenitor cells, have been implicated in homeostasis of the microvasculature. Decreased levels of circulating endothelial progenitor cells, associated with aging and/or cardiovascular risk factors, correlate with poor clinical outcomes in a range of cardiovascular diseases. Herein, we transplanted bone marrow cells from young stroke-prone spontaneously hypertensive rats (SHR-SP) into aged SHR-SP, the latter not exposed to radiation or chemotherapy. Analysis of recipient peripheral blood 28 days after transplantation revealed that 5% of circulating blood cells were of donor origin. Cerebral infarction was induced on day 30 posttransplantation. Animals transplanted with bone marrow from young SHR-SP displayed an increase in density of the microvasculature in the periinfarction zone, reduced ischemic brain damage and improved neurologic function. In vitro analysis revealed enhanced activation of endothelial nitric oxide synthase and reduced activation p38 microtubule-associated protein (MAP) kinase, the latter associated with endothelial apoptosis, in cultures exposed to bone marrow-derived mononuclear cells from young animals versus cells from aged counterparts. Our findings indicate that partial rejuvenation of bone marrow from aged rats with cells from young animals enhances the response to ischemic injury, potentially at the level of endothelial/vascular activation, providing insight into a novel approach ameliorate chronic vascular diseases.
Taguchi
Akihiko
A
Department of Regenerative Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan. taguchi@ri.ncvc.go.jp
Zhu
Pengxiang
P
Cao
Fang
F
Kikuchi-Taura
Akie
A
Kasahara
Yukiko
Y
Stern
David M
DM
Soma
Toshihiro
T
Matsuyama
Tomohiro
T
Hata
Ryuji
R
D000375:Aging; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000379:methods; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D002540:Cerebral Cortex / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D004789:Enzyme Activation; D017404:In Situ Hybridization, Fluorescence; D018836:Inflammation Mediators / Q000378:metabolism; D007267:Injections; D008297:Male; D008833:Microcirculation; D009420:Nervous System / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D012867:Skin / Q000293:injuries / Q000503:physiopathology; D020521:Stroke / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D015996:Survival Rate; D014945:Wound Healing; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D018836:Inflammation Mediators; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases