title: PACAP38/PAC1 signaling induces bone marrow-derived cells homing to ischemic brain.
abstract: Understanding stem cell homing, which is governed by environmental signals from the surrounding niche, is important for developing effective stem cell-based repair strategies. The molecular mechanism by which the brain under ischemic stress recruits bone marrow-derived cells (BMDCs) to the vascular niche remains poorly characterized. Here we report that hypoxia-inducible factor-1α (HIF-1α) activation upregulates pituitary adenylate cyclase-activating peptide 38 (PACAP38), which in turn activates PACAP type 1 receptor (PAC1) under hypoxia in vitro and cerebral ischemia in vivo. BMDCs homing to endothelial cells in the ischemic brain are mediated by HIF-1α activation of the PACAP38-PAC1 signaling cascade followed by upregulation of cellular prion protein and α6-integrin to enhance the ability of BMDCs to bind laminin in the vascular niche. Exogenous PACAP38 confers a similar effect in facilitating BMDCs homing into the ischemic brain, resulting in reduction of ischemic brain injury. These findings suggest a novel HIF-1α-activated PACAP38-PAC1 signaling process in initiating BMDCs homing into the ischemic brain for reducing brain injury and enhancing functional recovery after ischemic stroke.
authors.affiliation: Center for Neuropsychiatry and Translational Medicine Research Center, China Medical University and Hospital, Taichung, Taiwan.
authors.forename: Chen-Huan
authors.initials: CH
authors.lastname: Lin
authors.forename: Lian
authors.initials: L
authors.lastname: Chiu
authors.forename: Hsu-Tung
authors.initials: HT
authors.lastname: Lee
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chiang
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Liu
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.forename: Shinn-Zong
authors.initials: SZ
authors.lastname: Lin
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Hsu
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Hsieh
authors.forename: Woei-Cherng
authors.initials: WC
authors.lastname: Shyu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000096:biosynthesis*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
keywords: Bone marrow-derived cells; Hypoxia-inducible factor-1α; PACAP38/PAC1 signaling; Stroke; Vascular niche