Lukasz Wlodarek1,2, Faisal J Alibhai1, Jun Wu1, Shu-Hong Li1, Ren-Ke Li1,2,3. 1. Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada. 2. Faculty of Medicine, Department weof Physiology, University of Toronto, Toronto, ON, Canada. 3. Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
Abstract
AIMS: To date, stroke remains one of the leading causes of death and disability worldwide. Nearly three-quarters of all strokes occur in the elderly (>65 years old), and a vast majority of these individuals develop debilitating cognitive impairments that can later progress into dementia. Currently, there are no therapies capable of reversing the cognitive complications which arise following a stroke. Instead, current treatment options focus on preventing secondary injuries, as opposed to improving functional recovery. METHODS: We reconstituted aged (20-month old) mice with Sca-1+ bone marrow (BM) hematopoietic stem cells isolated from aged or young (2-month old) EGFP+ donor mice. Three months later the chimeric aged mice underwent cerebral ischemia/reperfusion by bilateral common carotid artery occlusion (BCCAO), after which cognitive function was evaluated. Immunohistochemical analysis was performed to evaluate host and recipient cells in the brain following BCCAO. RESULTS: Young Sca-1+ cells migrate to the aged brain and give rise to beneficial microglial-like cells that ameliorate stroke-induced loss of cognitive function on tasks targeting the hippocampus and cerebellum. We also found that young Sca-1+ cell-derived microglial-like cells possess neuroprotective properties as they do not undergo microgliosis upon migrating to the ischemic hippocampus, whereas the cells originating from old Sca-1+ cells proliferate extensively and skew toward a pro-inflammatory phenotype following injury. CONCLUSIONS: This study provides a proof-of-principle demonstrating that young BM Sca-1+ cells play a pivotal role in reversing stroke-induced cognitive impairments and protect the aged brain against secondary injury by attenuating the host cell response to injury.
AIMS: To date, stroke remains one of the leading causes of death and disability worldwide. Nearly three-quarters of all strokes occur in the elderly (>65 years old), and a vast majority of these individuals develop debilitating cognitive impairments that can later progress into dementia. Currently, there are no therapies capable of reversing the cognitive complications which arise following a stroke. Instead, current treatment options focus on preventing secondary injuries, as opposed to improving functional recovery. METHODS: We reconstituted aged (20-month old) mice with Sca-1+ bone marrow (BM) hematopoietic stem cells isolated from aged or young (2-month old) EGFP+ donor mice. Three months later the chimeric aged mice underwent cerebral ischemia/reperfusion by bilateral common carotid artery occlusion (BCCAO), after which cognitive function was evaluated. Immunohistochemical analysis was performed to evaluate host and recipient cells in the brain following BCCAO. RESULTS: Young Sca-1+ cells migrate to the aged brain and give rise to beneficial microglial-like cells that ameliorate stroke-induced loss of cognitive function on tasks targeting the hippocampus and cerebellum. We also found that young Sca-1+ cell-derived microglial-like cells possess neuroprotective properties as they do not undergo microgliosis upon migrating to the ischemic hippocampus, whereas the cells originating from old Sca-1+ cells proliferate extensively and skew toward a pro-inflammatory phenotype following injury. CONCLUSIONS: This study provides a proof-of-principle demonstrating that young BM Sca-1+ cells play a pivotal role in reversing stroke-induced cognitive impairments and protect the aged brain against secondary injury by attenuating the host cell response to injury.
Authors: Emelia J Benjamin; Salim S Virani; Clifton W Callaway; Alanna M Chamberlain; Alexander R Chang; Susan Cheng; Stephanie E Chiuve; Mary Cushman; Francesca N Delling; Rajat Deo; Sarah D de Ferranti; Jane F Ferguson; Myriam Fornage; Cathleen Gillespie; Carmen R Isasi; Monik C Jiménez; Lori Chaffin Jordan; Suzanne E Judd; Daniel Lackland; Judith H Lichtman; Lynda Lisabeth; Simin Liu; Chris T Longenecker; Pamela L Lutsey; Jason S Mackey; David B Matchar; Kunihiro Matsushita; Michael E Mussolino; Khurram Nasir; Martin O'Flaherty; Latha P Palaniappan; Ambarish Pandey; Dilip K Pandey; Mathew J Reeves; Matthew D Ritchey; Carlos J Rodriguez; Gregory A Roth; Wayne D Rosamond; Uchechukwu K A Sampson; Gary M Satou; Svati H Shah; Nicole L Spartano; David L Tirschwell; Connie W Tsao; Jenifer H Voeks; Joshua Z Willey; John T Wilkins; Jason Hy Wu; Heather M Alger; Sally S Wong; Paul Muntner Journal: Circulation Date: 2018-01-31 Impact factor: 29.690
Authors: Mohammed Yousufuddin; Adam C Bartley; Mouaz Alsawas; Heather L Sheely; Jessica Shultz; Paul Y Takahashi; Nathan P Young; M Hassan Murad Journal: J Stroke Cerebrovasc Dis Date: 2017-03-08 Impact factor: 2.136
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