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: Chen-Huan Lin, Lian Chiu, Hsu-Tung Lee, Chun-Wei Chiang, Shih-Ping Liu, Yung-Hsiang Hsu, Shinn-Zong Lin, Chung Y Hsu, Chia-Hung Hsieh, Woei-Cherng Shyu
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 33 Issue 4 Pg. 1153-72 (Apr 2015) ISSN: 1549-4918 [Electronic] England
• PMID: 25523790 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. STEM CELLS Published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Chemical References

• Pituitary Adenylate Cyclase-Activating Polypeptide
• Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I

Topics

• Animals
• Bone Marrow Cells (metabolism)
• Brain (metabolism, pathology)
• Brain Ischemia (metabolism)
• Cells, Cultured
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Pituitary Adenylate Cyclase-Activating Polypeptide (biosynthesis)
• Rats
• Rats, Sprague-Dawley
• Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I (biosynthesis)
• Signal Transduction (physiology)