AKAP12 mediates barrier functions of fibrotic scars during CNS repair.
The repair process after CNS injury shows a well-organized cascade of three distinct stages: inflammation, new tissue formation, and remodeling. In the new tissue formation stage, various cells migrate and form the fibrotic scar surrounding the lesion site. The fibrotic scar is known as an obstacle for axonal regeneration in the remodeling stage. However, the role of the fibrotic scar in the new tissue formation stage remains largely unknown. We found that the number of A-kinase anchoring protein 12 (AKAP12)-positive cells in the fibrotic scar was increased over time, and the cells formed a structure which traps various immune cells. Furthermore, the AKAP12-positive cells strongly express junction proteins which enable the structure to function as a physical barrier. In in vivo validation, AKAP12 knock-out (KO) mice showed leakage from a lesion, resulting from an impaired structure with the loss of the junction complex. Consistently, focal brain injury in the AKAP12 KO mice led to extended inflammation and more severe tissue damage compared to the wild type (WT) mice. Accordingly, our results suggest that AKAP12-positive cells in the fibrotic scar may restrict excessive inflammation, demonstrating certain mechanisms that could underlie the beneficial actions of the fibrotic scar in the new tissue formation stage during the CNS repair process.
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Jong-Ho
JH
Cha
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Hee-Jun
HJ
Wee
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea; Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.
Ji Hae
JH
Seo
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Bum Ju
BJ
Ahn
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Ji-Hyeon
JH
Park
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
Jun-Mo
JM
Yang
Department of Internal Medicine, and Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Korea.
Sae-Won
SW
Lee
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea; Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University College of Medicine, Seoul, Korea; Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
Eun Hee
EH
Kim
Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University College of Medicine, Seoul, Korea.
Ok-Hee
OH
Lee
Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea; Severance Integrative Research Institute for Cerebral & Cardiovascular Disease, Yonsei University College of Medicine, Seoul, Korea; Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
Ji Hoe
JH
Heo
College of Pharmacy, Inje University, Gimhae, Korea.
Hyo-Jong
HJ
Lee
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Irwin H
IH
Gelman
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.
Ken
K
Arai
Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America.
Eng H
EH
Lo
SNU-Harvard NeuroVascular Protection Research Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Korea.
Kyu-Won
KW
Kim
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism*; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017208:Rats, Wistar; D014945:Wound Healing / Q000235:genetics / Q000502:physiology
D054758:A Kinase Anchor Proteins; C491161:Akap12 protein, mouse; D018797:Cell Cycle Proteins