title: Hypoxic Preconditioning Augments the Therapeutic Efficacy of Bone Marrow Stromal Cells in a Rat Ischemic Stroke Model.
abstract: Transplantation of bone marrow stromal cells (BMSCs) is a promising therapy for ischemic stroke, but the poor oxygen environment in brain lesions limits the efficacy of cell-based therapies. Here, we tested whether hypoxic preconditioning (HP) could augment the efficacy of BMSC transplantation in a rat ischemic stroke model and investigated the underlying mechanism of the effect of HP. In vitro, BMSCs were divided into five passage (P0, P1, P2, P3, and P4) groups, and HP was applied to the groups by incubating the cells with 1% oxygen for 0, 4, 8, 12, and 24 h, respectively. We demonstrated that the expression of hypoxia-inducible factor-1α (HIF-1α) was increased in the HP-treated BMSCs, while their viability was unchanged. We also found that HP decreased the apoptosis of BMSCs during subsequent simulated ischemia-reperfusion (I/R) injury, especially in the 8-h HP group. In vivo, a rat transient focal cerebral ischemia model was established. These rats were administered normal cultured BMSCs (N-BMSCs), HP-treated BMSCs (H-BMSCs), or DMEM cell culture medium (control) at 24 h after the ischemic insult. Compared with the DMEM control group, the two BMSC-transplanted groups exhibited significantly improved functional recovery and reduced infarct volume, especially the H-BMSC group. Moreover, HP decreased neuronal apoptosis and enhanced the expression of BDNF and VEGF in the ischemic brain. Survival and differentiation of transplanted BMSCs were also increased by HP, and the quantity of engrafted BMSCs was significantly correlated with neurological function improvement. These results suggest that HP may enhance the therapeutic efficacy of BMSCs in an ischemic stroke model. The underlying mechanism likely involves the inhibition of caspase-3 activation and an increasing expression of HIF-1α, which promotes angiogenesis and neurogenesis and thereby reduces neuronal death and improves neurological function.
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China.|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China. lihuashen139@yeah.net.
authors.forename: Lihua
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China.
authors.forename: Wensen
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China.
authors.forename: Erbing
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Neurology, Affiliated Hospital of Nantong University, 20 XiSi Road, Nantong, 226001, China.
authors.forename: Kefu
authors.initials: K
authors.lastname: Cai
authors.affiliation: Department of Neuropharmacology, Institute of Nautical Medicine, Nantong University, 9 Seyuan Road, Nantong, 226019, Jiangsu, China. wgh036@hotmail.com.|Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA. wgh036@hotmail.com.
authors.forename: Guohua
authors.identifier: http://orcid.org/0000-0002-4810-8534
authors.initials: G
authors.lastname: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000150:complications* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D000860:Hypoxia / Q000150:complications / Q000473:pathology*; D019194:Ischemic Preconditioning; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018919:Neovascularization, Physiologic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000150:complications* / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D042461:Vascular Endothelial Growth Factor A; D053148:Caspase 3
keywords: Angiogenesis; Bone marrow stromal cells (BMSCs); Hypoxic preconditioning (HP); Ischemic stroke; Neurogenesis