title: Human Muse Cells Reconstruct Neuronal Circuitry in Subacute Lacunar Stroke Model.
abstract: Multilineage-differentiating stress-enduring (muse) cells are endogenous nontumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3+cells from the bone marrow from cultured bone marrow-mesenchymal stem cells. After transplantation into neurological disease models, muse cells exert repair effects, but the exact mechanism remains inconclusive.
  
  
  
  We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human bone marrow-muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice.
  
  
  
  Approximately 28% of initially transplanted muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (≈62%), MAP2 (≈30%), and GST-pi (≈12%). Dextran tracing revealed connections between host neurons and muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side, and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human-specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation.
  
  
  
  Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.).
authors.forename: Hiroki
authors.initials: H
authors.lastname: Uchida
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.).
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.).
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kushida
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Wakao
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.).
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.). mdezawa@med.tohoku.ac.jp cborlong@health.usf.edu.
authors.forename: Cesario V
authors.initials: CV
authors.lastname: Borlongan
authors.affiliation: From the Department of Stem Cell Biology and Histology (H.U., S.W., M.D.), Department of Neurosurgery (H.U., K.N., T.T.), and Department of Anatomy and Anthropology (Y.K., M.D.), Tohoku University Graduate School of Medicine, Sendai, Japan; and Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa (C.V.B.). mdezawa@med.tohoku.ac.jp cborlong@health.usf.edu.
authors.forename: Mari
authors.initials: M
authors.lastname: Dezawa
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000473:pathology / Q000502:physiology*; D019070:Cell Lineage; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000502:physiology; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009415:Nerve Net / Q000502:physiology*; D059409:Stroke, Lacunar / Q000473:pathology / Q000628:therapy*
keywords: brain ischemia; cerebral infarction; regeneration; stem cells; stroke, lacunar