title: Neurorestorative Responses to Delayed Human Mesenchymal Stromal Cells Treatment of Stroke in Type 2 Diabetic Rats.
abstract: Comorbidity of diabetes mellitus and stroke results in worse functional outcome, poor long-term recovery, and extensive vascular damage. We investigated the neurorestorative effects and mechanisms of stroke treatment with human bone marrow-derived mesenchymal stromal cells (hMSCs) in type 2 diabetes mellitus (T2DM) rats.
  
  
  
  Adult male Wistar rats were induced with T2DM, subjected to 2 hours of middle cerebral artery occlusion (MCAo) and treated via tail-vein injection with (1) PBS (n=8) and (2) hMSCs (n=10; 5×106) at 3 days after MCAo.
  
  
  
  In T2DM rats, hMSCs administered at 3 days after MCAo significantly improves neurological function without affecting blood glucose, infarct volume, and incidence of brain hemorrhage in comparison to T2DM-MCAo PBS-treated rats. Delayed hMSC treatment of T2DM stroke significantly improves blood-brain barrier integrity, increases vascular and arterial density and cerebral vascular perfusion, and promotes neuroblast cell migration and white matter remodeling as indicated by increased doublecortin, axon, myelin, and neurofilament density, respectively. Delayed hMSC treatment significantly increases platelet-derived growth factor expression in the ischemic brain, decreases proinflammatory M1 macrophage and increases anti-inflammatory M2 macrophage compared to PBS-treated T2DM-MCAo rats. In vitro data show that hMSCs increase subventricular zone explant cell migration and primary cortical neuron neurite outgrowth, whereas inhibition of platelet-derived growth factor decreases hMSC-induced subventricular zone cell migration and axonal outgrowth.
  
  
  
  In T2DM stroke rats, delayed hMSC treatment significantly improves neurological functional outcome and increases neurorestorative effects and M2 macrophage polarization. Increasing brain platelet-derived growth factor expression may contribute to hMSC-induced neurorestoration.
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Tao
authors.initials: T
authors.lastname: Yan
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Poornima
authors.initials: P
authors.lastname: Venkat
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Ruizhuo
authors.initials: R
authors.lastname: Ning
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.).
authors.forename: Mei
authors.initials: M
authors.lastname: Lu
authors.affiliation: From the Tianjin Neurological and Gerontology Institute, Department of Neurology of Tianjin Medical University General Hospital, China (T.Y., J.C.); Department of Neurology (T.Y., P.V., M.C., A.Z., R.N., C.R., Y.Z., J.C.) and Department of Biostatistics and Research Epidemiology (M.L.), Henry Ford Hospital, Detroit, MI; and Department of Physics, Oakland University, Rochester, MI (M.C.). jieli@neuro.hfh.edu.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D018919:Neovascularization, Physiologic; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D020521:Stroke / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*
keywords: diabetes mellitus, type 2; ischemia; mesenchymal stromal cells; platelet-derived growth factor; stroke