Hiroki Uchida1, Kuniyasu Niizuma1, Yoshihiro Kushida1, Shohei Wakao1, Teiji Tominaga1, Cesario V Borlongan2, Mari Dezawa2. 1. 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.). 2. 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.
Abstract
BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND PURPOSE: 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. METHODS: 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 immunodeficientmice. RESULTS: 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 strokemice 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. CONCLUSIONS: 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.
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