High-mobility group box 1 from reactive astrocytes enhances the accumulation of endothelial progenitor cells in damaged white matter.

Abstract

High-mobility group box 1 (HMGB1) was initially described as a damage-associated-molecular-pattern (DAMP) mediator that worsens acute brain injury after stroke. But, recent findings suggest that HMGB1 can play a surprisingly beneficial role during stroke recovery by promoting endothelial progenitor cell (EPC) function and vascular remodeling in cortical gray matter. Here, we ask whether HMGB1 may also influence EPC responses in white matter injury. The standard lysophosphatidylcholine (LPC) injection model was used to induce focal demyelination in the corpus callosum of mice. Immunostaining showed that within the focal white matter lesions, HMGB1 was up-regulated in GFAP-positive reactive astrocytes, along with the accumulation of Flk1/CD34-double-positive EPCs that expressed pro-recovery mediators such as brain-derived neurotrophic factor and basic fibroblast growth factor. Astrocyte-EPC signaling required the HMGB1 receptor RAGE as treatment with RAGE-neutralizing antibody significantly decreased EPC accumulation. Moreover, suppression of HMGB1 with siRNA in vivo significantly decreased EPC numbers in damaged white matter as well as proliferated endothelial cell numbers. Finally, in vitro cell culture systems confirmed that HMGB1 directly affected EPC function such as migration and tube formation. Taken together, our findings suggest that HMGB1 from reactive astrocytes may attract EPCs to promote recovery after white matter injury.

• Authors: Kazuhide Hayakawa, Nobukazu Miyamoto, Ji Hae Seo, Loc-Duyen D Pham, Kyu-Won Kim, Eng H Lo, Ken Arai
• Journal: Journal of neurochemistry (J Neurochem) Vol. 125 Issue 2 Pg. 273-80 (Apr 2013) ISSN: 1471-4159 [Electronic] England
• PMID: 23227954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 International Society for Neurochemistry.

Chemical References

• HMGB1 Protein
• RNA, Small Interfering

Topics

• Animals
• Astrocytes (metabolism)
• Blotting, Western
• Brain Injuries (metabolism)
• Disease Models, Animal
• Endothelial Progenitor Cells (metabolism)
• Flow Cytometry
• HMGB1 Protein (metabolism)
• Humans
• Immunohistochemistry
• Male
• Mice
• Mice, Inbred C57BL
• RNA, Small Interfering
• Rats
• White Matter (injuries, metabolism)