title: Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice.
abstract: Intracerebral hemorrhagic stroke (ICH) causes high mortality and morbidity with very limited treatment options. Cell-based therapy has emerged as a novel approach to replace damaged brain tissues and promote regenerative processes. In this study we tested the hypothesis that intranasally delivered hypoxia-preconditioned BMSCs could reach the brain, promote tissue repair and improve functional recovery after ICH. Hemorrhagic stroke was induced in adult C57/B6 mice by injection of collagenase IV into the striatum. Animals were randomly divided into three groups: sham group, intranasal BMSC treatment group, and vehicle treatment group. BMSCs were pre-treated with hypoxic preconditioning (HP) and pre-labeled with Hoechst before transplantation. Behavior tests, including the mNSS score, rotarod test, adhesive removal test, and locomotor function evaluation were performed at varying days, up to 21days, after ICH to evaluate the therapeutic effects of BMSC transplantation. Western blots and immunohistochemistry were performed to analyze the neurotrophic effects. Intranasally delivered HP-BMSCs were identified in peri-injury regions. NeuN+/BrdU+ co-labeled cells were markedly increased around the hematoma region, and growth factors, including BDNF, GDNF, and VEGF were significantly upregulated in the ICH brain after BMSC treatment. The BMSC treatment group showed significant improvement in behavioral performance compared with the vehicle group. Our data also showed that intranasally delivered HP-BMSCs migrated to peri-injury regions and provided growth factors to increase neurogenesis after ICH. We conclude that intranasal administration of BMSC is an effective treatment for ICH, and that it enhanced neuroregenerative effects and promoted neurological functional recovery after ICH. Overall, the investigation supports the potential therapeutic strategy for BMSC transplantation therapy against hemorrhagic stroke.
authors: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Jinmei
authors: J
authors: Sun
authors: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Zheng Zachory
authors: ZZ
authors: Wei
authors: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: Xiaohuan
authors: X
authors: Gu
authors: Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors: James Ya
authors: JY
authors: Zhang
authors: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
authors: Yongbo
authors: Y
authors: Zhang
authors: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: jimeili2002@163.com.
authors: Jimei
authors: J
authors: Li
authors: Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Laboratories of Stem Cell Biology and Neural Regeneration and Function Recovery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: lwei7@emory.edu.
authors: Ling
authors: L
authors: Wei
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001921:Brain / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000150:complications*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D005786:Gene Expression Regulation; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity; D009422:Nervous System Diseases / Q000209:etiology; D055495:Neurogenesis / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D011597:Psychomotor Performance; D020127:Recovery of Function; D020521:Stroke / Q000209:etiology* / Q000628:therapy*; D013997:Time Factors
chemical_list: D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides
keywords: Hypoxic preconditioning; Intracerebral hemorrhage; Intranasal transplantation; Neurogenesis; Stroke