title: Neurorestorative Therapy of Stroke in Type 2 Diabetes Mellitus Rats Treated With Human Umbilical Cord Blood Cells.
abstract: OBJECTIVE
  Diabetes mellitus is a high-risk factor for ischemic stroke. Diabetic stroke patients suffer worse outcomes, poor long-term recovery, risk of recurrent strokes, and extensive vascular damage. We investigated the neurorestorative effects and the underlying mechanisms of stroke treatment with human umbilical cord blood cells (HUCBCs) in type 2 diabetes mellitus (T2DM) rats.
  
  
  METHODS
  Adult male T2DM rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo). Three days after MCAo, rats were treated via tail-vein injection with (1) PBS and (2) HUCBCs (5×10(6)), n=10 per group.
  
  
  RESULTS
  HUCBC stroke treatment initiated 3 days after MCAo in T2DM rats did not significantly decrease blood-brain barrier leakage (P=0.1) and lesion volume (P=0.078), but significantly improved long-term functional outcome and decreased brain hemorrhage (P<0.05) when compared with the PBS-treated T2DM MCAo control group. HUCBC treatment significantly promoted white matter remodeling as indicated by increased expression of Bielschowsky silver (axons marker), Luxol fast blue (myelin marker), SMI-31 (neurofilament), and Synaptophysin in the ischemic border zone. HUCBC promoted vascular remodeling and significantly increased arterial and vascular density. HUCBC treatment of stroke in T2DM rats significantly increased M2 macrophage polarization (increased M2 macrophage, CD163and CD 206; decreased M1 macrophage, ED1 and inducible nitric oxide synthase expression) in the ischemic brain compared with PBS-treated T2DM MCAo controls (P<0.05). HUCBC also significantly decreased proinflammatory factors, that is, matrix metalloproteinase 9, receptor for advanced glycation end products and toll-like receptor 4 expression in the ischemic brain.
  
  
  CONCLUSIONS
  HUCBC treatment initiated 3 days after stroke significantly increased white matter and vascular remodeling in the ischemic brain as well as decreased neuroinflammatory factor expression in the ischemic brain in T2DM rats and promoted M2 macrophage polarization. HUCBC reduction of neuroinflammation and increased vascular and white matter axonal remodeling may contribute to the HUCBC-induced beneficial effects in T2DM stroke rats.
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Tao
authors.initials: T
authors.lastname: Yan
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Poornima
authors.initials: P
authors.lastname: Venkat
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Alex
authors.initials: A
authors.lastname: Zacharek
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Ruizhuo
authors.initials: R
authors.lastname: Ning
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Cui
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Cynthia
authors.initials: C
authors.lastname: Roberts
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Nicole
authors.initials: N
authors.lastname: Kuzmin-Nichols
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.).
authors.forename: Cyndy Davis
authors.initials: CD
authors.lastname: Sanberg
authors.affiliation: From the Department of Neurology, Henry Ford Hospital, Detroit, MI (T.Y., P.V., M.C., A.Z., R.N., Y.C., C.R., J.C.); Tianjin Neurological Institute, Neurology of Tianjin Medical University General Hospital, Tianjin, China (T.Y., J.C.); Department of Physics, Oakland University, Rochester, MI (P.V., M.C.); and Saneron CCEL Therapeutics Inc, Tampa, FL (N.K.-N., C.D.S.). jieli@neuro.hfh.edu.
authors.forename: Jieli
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000628:therapy*; D036101:Cord Blood Stem Cell Transplantation / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000209:etiology / Q000628:therapy; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000209:etiology / Q000628:therapy*
keywords: diabetes mellitus, type 2; human umbilical cord blood; infarction, middle cerebral artery; matrix metalloproteinase 9; neurorestorative therapy; stroke; vascular remodeling