Meningeal Fibrosis in the Axolotl Spinal Cord: Extracellular Matrix and Cellular Responses

Abstract

Though mammalian spinal cord injury (SCI) has long been a topic of study, effective therapies that promote functional recovery are not yet available. The axolotl, Ambystoma mexicanum, is a valuable animal model in the investigation of spinal cord regeneration, as this urodele is able to achieve functional recovery even after complete spinal cord transection. Understanding the similarities and differences between the mammalian SCI response and that of the axolotl provides insight into the process of successful regeneration, and bolsters the fundamental knowledge used in the development of future mammalian SCI treatments. This thesis provides a detailed analysis of the ultrastructure of the axolotl meninges, as this has not yet been presented in existing literature, and reveals that the axolotl meninges consist of 3 distinct layers as does mammalian meninges; the dura mater, arachnoid mater, and pia mater. The role of reactive meningeal and ependymal cells is also investigated in regard to the deposition and remodeling of the fibrotic ECM, which is found to be similar in composition to hydrogel scaffolds being studied in mammalian SCI. It is shown that meningeal fibroblasts are the primary source of the extensive fibrillar collagen deposition that fills the entire spinal canal, peaking at approximately 3 weeks post transection and remaining until approximately 5 weeks post transection, and that there is no deposition of type IV collagen within the lesion site. Mesenchymal ependymal cells are shown to contribute to the ECM deposition through the production of glycosaminoglycans that are used in sidechains of both unsulfated and sulfated proteoglycans, while simultaneously remodeling the ECM through the production of MMPs and phagocytosis of cellular debris. Further, this study shows that mesenchymal ependymal cells and a population of foamy macrophages contribute to the degradation of the fibrin clot that forms in the acute phase of injury, and that this fibrin clot provides a necessary and permissive substrate for early mesenchymal outgrowth.