Abstract
Under physiological conditions, lymphatic vessels are thought to be absent from the central nervous system (CNS), although they are widely distributed within the rest of the body. Recent work in the eye, i.e., another organ regarded as alymphatic, revealed numerous cells expressing lymphatic markers. As the latter can be involved in the response to pathological conditions, we addressed the presence of cells expressing lymphatic markers within the spinal cord by immunohistochemistry. Spinal cord of young adult Fisher rats was scrutinized for the co-expression of the lymphatic markers PROX1 and LYVE-1 with the cell type markers Iba1, CD68, PGP9.5, OLIG2. Rat skin served as positive control for the lymphatic markers. PROX1-immunoreactivity was detected in many nuclei throughout the spinal cord white and gray matter. These nuclei showed no association with LYVE-1. Expression of LYVE-1 could only be detected in cells at the spinal cord surface and in cells closely associated with blood vessels. These cells were found to co-express Iba1, a macrophage and microglia marker. Further, double labeling experiments using CD68, another marker found in microglia and macrophages, also displayed co-localization in the Iba1+ cells located at the spinal cord surface and those apposed to blood vessels. On the other hand, PROX1-expressing cells found in the parenchyma were lacking Iba1 or PGP9.5, but a significant fraction of those cells showed co-expression of the oligodendrocyte lineage marker OLIG2. Intriguingly, following spinal cord injury, LYVE-1-expressing cells assembled and reorganized into putative pre-vessel structures. As expected, the rat skin used as positive controls revealed classical lymphatic vessels, displaying PROX1+ nuclei surrounded by LYVE-1-immunoreactivity. Classical lymphatics were not detected in adult rat spinal cord. Nevertheless, numerous cells expressing either LYVE-1 or PROX1 were identified. Based on their localization and overlapping expression with Iba1, the LYVE-1+ cell population likely represents a macrophage subpopulation, while a significant fraction of PROX1+ cells belong to the oligodendrocytic lineage based on their distribution and the expression of OLIG2. The response of these LYVE-1+ and PROX1+ cell subpopulations to pathological conditions, especially in spinal cord inflammatory conditions, needs to be further elucidated.
Highlights
MATERIALS AND METHODSTwo crucial roles are carried out by the lymphatic system: (1) fluid homeostasis via the drainage of extracellular fluid; and (2) immune defense through the transport of antigens and immune cells to the lymph nodes (Alitalo, 2011; Card et al, 2014)
We chose for this study the combination of the transcription factor PROX1, a homeo-box protein that retains its activity in nuclei of lymphatic endothelium in adulthood (Wigle and Oliver, 1999; Wilting et al, 2002) and LYVE-1, a membrane-bound glycoprotein and one of the best characterized markers of lymphatic endothelium (Jackson, 2004; Baluk and McDonald, 2008)
Identical results were obtained on the dorsal side of the spinal cord, i.e., LYVE-1immunoreactive cells were detected on the spinal cord surface and in association with vessels of the dorsal spinal arteries entering the parenchyma (Figures 1G,H)
Summary
MATERIALS AND METHODSTwo crucial roles are carried out by the lymphatic system: (1) fluid homeostasis via the drainage of extracellular fluid; and (2) immune defense through the transport of antigens and immune cells to the lymph nodes (Alitalo, 2011; Card et al, 2014). Being part of the CNS, which is considered to be alymphatic, the existence of structures or cells expressing lymphatic markers has not been thoroughly investigated within the spinal cord. Detection of the lymphatic endothelial marker LYVE-1 revealed numerous LYVE-1-expressing cells on the surface of the spinal cord, surrounding the ventral spinal artery, and following the sulcal arteries into the anterior median sulcus (Figure 1D).
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