title: Role of HIF-1α-activated Epac1 on HSC-mediated neuroplasticity in stroke model.
abstract: Exchange protein activated by cAMP-1 (Epac1) plays an important role in cell proliferation, cell survival and neuronal signaling, and activation of Epac1 in endothelial progenitor cells increases their homing to ischemic muscles and promotes neovascularization in a model of hind limb ischemia. Moreover, upregulation of Epac1 occurs during organ development and in diseases such as myocardial hypertrophy, diabetes, and Alzheimer's disease. We report here that hypoxia upregulated Epac1 through HIF-1α induction in the CD34-immunosorted human umbilical cord blood hematopoietic stem cells (hUCB(34)). Importantly, implantation of hUCB(34) subjected to hypoxia-preconditioning (HP-hUCB(34)) improved stroke outcome, more than did implantation of untreated hUCB(34), in rodents subjected to cerebral ischemia, and this required Epac1-to-matrix metalloprotease (MMP) signaling. This improved therapeutic efficacy correlated with better engraftment and differentiation of these cells in the ischemic host brain. In addition, more than did implantation of untreated HP-hUCB(34), implantation of HP-hUCB(34) improved cerebral blood flow into the ischemic brain via induction of angiogenesis, facilitated proliferation/recruitment of endogenous neural progenitor cells in the ischemic brain, and promoted neurite outgrowth following cerebral ischemia. Consistent with our proposed role of Epac1-to-MMP signaling in hypoxia-preconditioning, the above mentioned effects of implanting HP-hUCB(34) could be abolished by pharmacological inhibition and genetic disruption/deletion of Epac1 or MMPs. We have discovered a HIF-1α-to-Epac1-to-MMP signaling pathway that is required for the improved therapeutic efficacy resulting from hypoxia preconditioning of hUCB(34) in vitro prior to their implantation into the host brain in vivo.
authors.affiliation: Department of Neurology, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chen-Huan
authors.initials: CH
authors.lastname: Lin
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.forename: Shin-Da
authors.initials: SD
authors.lastname: Lee
authors.forename: Wei
authors.initials: W
authors.lastname: Lee
authors.forename: Chin-Wen Chental
authors.initials: CW
authors.lastname: Cho
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Hsiao-Jung
authors.initials: HJ
authors.lastname: Wang
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.forename: Ching-Yuan
authors.initials: CY
authors.lastname: Su
authors.forename: Yung-Luen
authors.initials: YL
authors.lastname: Yu
authors.forename: Chung-Y
authors.initials: CY
authors.lastname: Hsu
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation; D036101:Cord Blood Stem Cell Transplantation; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000000981:diagnostic imaging / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000172:deficiency; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics; D009473:Neuronal Plasticity / Q000502:physiology*; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D050257:Tubulin Modulators / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D018952:Antigens, CD34; D020662:Guanine Nucleotide Exchange Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C116122:RAPGEF3 protein, human; D050257:Tubulin Modulators; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004958:Estradiol; D000077584:2-Methoxyestradiol; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D005947:Glucose
keywords: CD34-immunosorted human umbilical cord blood hematopoietic stem cells; Cerebral ischemia; Epac1; Hypoxia preconditioning (HP); Immunoselection of CD34; exchange protein activated by cAMP; hUCB; hUCB(34); human umbilical cord blood