PACAP38/PAC1 Signaling Induces Bone Marrow‐Derived Cells Homing to Ischemic Brain

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...

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Bibliographic Details
Published in:Stem cells (Dayton, Ohio) Ohio), 2015-04, Vol.33 (4), p.1153-1172
Main Authors: Lin, Chen-Huan, Chiu, Lian, Lee, Hsu-Tung, Chiang, Chun-Wei, Liu, Shih-Ping, Hsu, Yung-Hsiang, Lin, Shinn-Zong, Hsu, Chung Y., Hsieh, Chia-Hung, Shyu, Woei-Cherng
Format: Article
Language:English
Subjects:
Animals
Bone marrow
Bone Marrow Cells - metabolism
Bone marrow‐derived cells
Brain - metabolism
Brain - pathology
Brain Ischemia - metabolism
Cells, Cultured
HEK293 Cells
Humans
Hypoxia
Hypoxia‐inducible factor‐1α
Male
Mice
Mice, Knockout
Mice, Transgenic
PACAP38/PAC1 signaling
Pituitary Adenylate Cyclase-Activating Polypeptide - biosynthesis
Rats
Rats, Sprague-Dawley
Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I - biosynthesis
Regenerative Medicine
Signal Transduction - physiology
Stem cells
Stroke
Traumatic brain injury
Vascular niche
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Summary: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. Stem Cells 2015;33:1153–1172
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.1915