PMID- 27153974 OWN - NLM STAT- MEDLINE DCOM- 20171106 LR - 20181113 IS - 1756-6606 (Electronic) IS - 1756-6606 (Linking) VI - 9 IP - 1 DP - 2016 May 6 TI - Rescuing macrophage normal function in spinal cord injury with embryonic stem cell conditioned media. PG - 48 LID - 10.1186/s13041-016-0233-3 [doi] LID - 48 AB - BACKGROUND: Macrophages play an important role in the inflammatory responses involved with spinal cord injury (SCI). We have previously demonstrated that infiltrated bone marrow-derived macrophages (BMDMs) engulf myelin debris, forming myelin-laden macrophages (mye-Mvarphi). These mye-Mvarphi promote disease progression through their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells. We thus hypothesize that the excessive accumulation of mye-Mvarphi is the root of secondary injury, and that targeting mye-Mvarphi represents an efficient strategy to improve the local inflammatory microenvironment in injured spinal cords and to further motor neuron function recovery. In this study, we administer murine embryonic stem cell conditioned media (ESC-M) as a cell-free stem cell based therapy to treat a mouse model of SCI. RESULTS: We showed that BMDMs, but not microglial cells, engulf myelin debris generated at the injury site. Phagocytosis of myelin debris leads to the formation of mye-Mvarphi in the injured spinal cord, which are surrounded by activated microglia cells. These mye-Mvarphi are pro-inflammatory and lose the normal macrophage phagocytic capacity for apoptotic cells. We therefore focus on how to trigger lipid efflux from mye-Mvarphi and thus restore their function. Using ESC-M as an immune modulating treatment for inflammatory damage after SCI, we rescued mye-Mvarphi function and improved functional locomotor recovery. ESC-M treatment on mye-Mvarphi resulted in improved exocytosis of internalized lipids and a normal capacity for apoptotic cell phagocytosis. Furthermore, when ESC-M was administered intraperitoneally after SCI, animals exhibited significant improvements in locomotor recovery. Examination of spinal cords of the ESC-M treated mice revealed similar improvements in macrophage function as well as a shift towards a more anti-inflammatory environment at the lesion and parenchyma. CONCLUSIONS: The embryonic stem cell conditioned media can be used as an effective treatment for SCI to resolve inflammation and improve functional recovery while circumventing the complications involved in whole cell transplantation. FAU - Guo, Lei AU - Guo L AD - Department of Orthopedics, The Second Affiliated Hospital of Xian Jiaotong University, Xian, 710004, China. AD - Department of Biomedical Sciences, Florida State University, College of Medicine, 1115 West Street, Tallahassee, FL, 32306, USA. FAU - Rolfe, Alyssa J AU - Rolfe AJ AD - Department of Biomedical Sciences, Florida State University, College of Medicine, 1115 West Street, Tallahassee, FL, 32306, USA. FAU - Wang, Xi AU - Wang X AD - W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08854, USA. FAU - Tai, Wenjiao AU - Tai W AD - Department of Biomedical Sciences, Florida State University, College of Medicine, 1115 West Street, Tallahassee, FL, 32306, USA. FAU - Cheng, Zhijian AU - Cheng Z AD - Department of Orthopedics, The Second Affiliated Hospital of Xian Jiaotong University, Xian, 710004, China. AD - Department of Biomedical Sciences, Florida State University, College of Medicine, 1115 West Street, Tallahassee, FL, 32306, USA. FAU - Cao, Kai AU - Cao K AD - Department of Orthopedics, The Second Affiliated Hospital of Xian Jiaotong University, Xian, 710004, China. FAU - Chen, Xiaoming AU - Chen X AD - Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Xu, Yunsheng AU - Xu Y AD - Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Sun, Dongming AU - Sun D AD - W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08854, USA. FAU - Li, Jinhua AU - Li J AD - Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia. FAU - He, Xijing AU - He X AD - Department of Orthopedics, The Second Affiliated Hospital of Xian Jiaotong University, Xian, 710004, China. FAU - Young, Wise AU - Young W AD - W. M. Keck Center for Collaborative Neuroscience, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08854, USA. FAU - Fan, Jianqing AU - Fan J AD - Statistical Laboratory, Princeton University, Princeton, NJ, 08540, USA. FAU - Ren, Yi AU - Ren Y AD - Department of Biomedical Sciences, Florida State University, College of Medicine, 1115 West Street, Tallahassee, FL, 32306, USA. yi.ren@med.fsu.edu. AD - Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. yi.ren@med.fsu.edu. LA - eng GR - R01 GM072611/GM/NIGMS NIH HHS/United States GR - R01 GM100474/GM/NIGMS NIH HHS/United States PT - Journal Article DEP - 20160506 PL - England TA - Mol Brain JT - Molecular brain JID - 101468876 RN - 0 (Culture Media, Conditioned) RN - 0 (Lipids) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Bone Marrow Cells/metabolism MH - Culture Media, Conditioned/*pharmacology MH - Foam Cells/drug effects/metabolism MH - Inflammation/complications/pathology MH - Lipids/chemistry MH - Macrophage Activation/drug effects MH - Macrophages/drug effects/metabolism/*pathology MH - Mice MH - Mice, Inbred C57BL MH - Mouse Embryonic Stem Cells/*metabolism MH - Myelin Sheath/metabolism MH - Neutrophils/drug effects/metabolism MH - Phagocytosis/drug effects MH - Recovery of Function/drug effects MH - Spinal Cord Injuries/pathology/*physiopathology/*therapy PMC - PMC4858887 OTO - NOTNLM OT - Bone Marrow-Derived Macrophages (BMDMs) OT - Embryonic Stem Cells (ESCs) OT - Inflammation OT - Microglia OT - Myelin OT - Spinal Cord Injury (SCI) EDAT- 2016/05/08 06:00 MHDA- 2017/11/07 06:00 PMCR- 2016/05/06 CRDT- 2016/05/08 06:00 PHST- 2016/03/08 00:00 [received] PHST- 2016/05/01 00:00 [accepted] PHST- 2016/05/08 06:00 [entrez] PHST- 2016/05/08 06:00 [pubmed] PHST- 2017/11/07 06:00 [medline] PHST- 2016/05/06 00:00 [pmc-release] AID - 10.1186/s13041-016-0233-3 [pii] AID - 233 [pii] AID - 10.1186/s13041-016-0233-3 [doi] PST - epublish SO - Mol Brain. 2016 May 6;9(1):48. doi: 10.1186/s13041-016-0233-3.