Abstract
BackgroundMacrophages 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-Mϕ). These mye-Mϕ 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-Mϕ is the root of secondary injury, and that targeting mye-Mϕ 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.ResultsWe 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-Mϕ in the injured spinal cord, which are surrounded by activated microglia cells. These mye-Mϕ are pro-inflammatory and lose the normal macrophage phagocytic capacity for apoptotic cells. We therefore focus on how to trigger lipid efflux from mye-Mϕ and thus restore their function. Using ESC-M as an immune modulating treatment for inflammatory damage after SCI, we rescued mye-Mϕ function and improved functional locomotor recovery. ESC-M treatment on mye-Mϕ 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.ConclusionsThe 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.
Highlights
Macrophages play an important role in the inflammatory responses involved with spinal cord injury (SCI)
We have shown that dysregulation of macrophage lipid homeostasis in the injured cord, is the major contributing factor of long term lipid retention. We propose that these pro-inflammatory myelin-laden macrophages are an important therapeutic target in SCI because of their reduced ability to clear apoptotic cells and myelin debris at the injury site
We have previously demonstrated that infiltrated bone marrow-derived macrophages (BMDMs) migrate to the epicenter of the injured spinal cord
Summary
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-Mφ). These mye-Mφ promote disease progression through their pro-inflammatory phenotype, enhanced neurotoxicity, and impaired phagocytic capacity for apoptotic cells. The secondary injury is characterized by a prolonged inflammatory response [4, 5], resulting in further tissue damage and neurodegeneration by resident microglia and infiltrated bone marrow-derived macrophages (BMDMs) [6]. The clearance of apoptotic cells and myelin debris is the responsibility of infiltrating macrophages, and to a lesser degree, resident microglia. Prompt clearance of the array of apoptotic cells and myelin debris by macrophages is critical to limit the inflammatory cascade and promote neuroregeneration [8]
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