title: Milk fat globule-EGF factor VIII attenuates CNS injury by promoting neural stem cell proliferation and migration after cerebral ischemia.
abstract: The mediators in activating neural stem cells during the regenerative process of neurogenesis following stroke have not been fully identified. Milk fat globule-EGF Factor VIII (MFG-E8), a secreted glycoprotein serves several cellular functions by binding to its receptor, αv β3-integrin. However, its role in regulating neural stem cells after stroke has not been determined yet. We therefore, aim to reveal whether MFG-E8 promotes neural stem cell proliferation and migration during stroke. Stroke was induced in wild-type (Wt) and MFG-E8-deficinet (Mfge8-/-) mice by transient middle cerebral artery occlusion (tMCAO). Commercially available recombinant mouse MFG-E8 (rmMFG-E8) was used for mechanistic assays in neural stem cell line, while the in house prepared recombinant human MFG-E8 (rhMFG-E8) was used for in vivo administration into rats with tMCAO. The in vitro effects of recombinant rmMFG-E8 for the neural stem cell proliferation and migration were determined by BrdU and transwell migration assay, respectively. The expression of cyclin D2, p53 and netrin-1, was analyzed by qPCR. We report that the treatment of rhMFG-E8 significantly improved the neurological deficit score, body weight lost and neural stem cell proliferation in a rat model of tMCAO. Conversely, decreased neural stem cell proliferation was observed in Mfge8-/- mice in comparison with the Wt counterparts underwent tMCAO. rmMFG-E8 stimulated the proliferation of mouse embryonic neural stem cells via upregulation of cyclin D2 and downregulation of p53, which is mediated by αv β3-integrin. rmMFG-E8 also promoted mouse embryonic neural stem cell migration via αv β3-integrin dependent manner in upregulating netrin-1. Our findings suggest MFG-E8 to promote neural stem cell proliferation and migration, which therefore establishes a promising therapeutic strategy for cerebral ischemia.
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors: Cletus
authors: C
authors: Cheyuo
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America; Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America.
authors: Monowar
authors: M
authors: Aziz
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America; Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America.
authors: Weng-Lang
authors: WL
authors: Yang
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America; Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America.
authors: Asha
authors: A
authors: Jacob
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America; Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America.
authors: Mian
authors: M
authors: Zhou
authors: Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America; Department of Surgery, Hofstra North Shore-Long Island Jewish School of Medicine, Manhasset, New York, United States of America.
authors: Ping
authors: P
authors: Wang
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000008:administration & dosage / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects*; D056742:Cyclin D2 / Q000378:metabolism; D057967:Infusions, Intraventricular; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008297:Male; D008894:Milk Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D009414:Nerve Growth Factors / Q000378:metabolism; D000075388:Netrin-1; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D056742:Cyclin D2; D039302:Integrin alphaVbeta3; C499941:MFGE8 protein, rat; D008894:Milk Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1