The Peripheral Lymphatic System Is Impaired by the Loss of Neuronal Control Associated with Chronic Spinal Cord Injury.

Spinal cord injury (SCI) is associated with venous vascular dysfunction below the level of injury, resulting in dysregulation of tissue fluid homeostasis in afflicted skin. The purpose of this study was to determine whether loss of neuronal control in chronic SCI also affects the skin lymphatic system. Morphology of lymphatics was characterized by immunohistochemistry and lymphatic gene expression profiles determined by DNA microarray analysis. In SCI, skin lymphatic function appeared to be impaired, because the ratio of functionally dilated versus collapsed lymphatic vessels was decreased 10-fold compared with control. Consequently, the average lumen area of lymphatic vessels was almost halved, possibly due to the known impaired connective tissue integrity of SCI skin. In fact, collagenases were found to be overexpressed in SCI skin, and dermal collagen structure was impaired. Molecular profiling also suggested an SCI-specific phenotype of increased connective tissue turnover and decreased lymphatic contractility. The total number of lymphatic vessels in SCI skin, however, was doubled, pointing to enhanced lymphangiogenesis. In conclusion, these data show, for the first time, that lymphatic function and development in human skin are under neuronal control. Because peripheral venous and lymphatic vascular defects are associated with disturbed fluid homeostasis, inappropriate wound healing reactions, and impaired skin immunity, they might contribute to the predisposition of afflicted individuals to pressure ulcer formation and wound healing disorders.

Cellular and molecular changes that predispose skin in chronic spinal cord injury to pressure ulcer formation.

Patients with spinal cord injury have a predisposition to develop pressure ulcers. Specific characteristics of the patients' skin potentially involved have not yet been identified. The purpose of this investigation was to determine whether loss of neuronal control affects cellular and molecular homeostasis in the skin. Intact afflicted skin, wound edge of pressure ulcers, and control skin were analysed. Platelets, transforming growth factor-ß1, and activin A were identified by immunohistochemistry. Transforming growth factor-ß-like activity was determined by bioassay, and gene expression by DNA microarray analysis or RT-PCR. In afflicted skin, enhanced platelet extravasation was detected. Transforming growth factor-ß1 and activin A accumulated in the dermal-epidermal junction zone. Transforming growth factor-ß-like activity and activin A expression were increased in intact afflicted skin (compared to control skin) and were further enhanced in pressure ulcers. In vitro, activity was generated by fibroblast-epithelial cell interactions, which also induced activin A. Thus, loss of neuronal control in spinal cord injury appears to trigger inappropriate wound healing processes in the patients' skin. Plasma leakage and increased transforming growth factor-ß-like activity combined with shear forces potentially enhance the risk for pressure ulcer formation.

A role for kinesin heavy chain in controlling vesicle transport into dendrites in Drosophila.

The unique architecture of neurons requires the establishment and maintenance of polarity, which relies in part on microtubule-based transport to deliver essential cargo into dendrites. To test different models of differential motor protein regulation and to understand how different compartments in neurons are supplied with necessary functional proteins, we studied mechanisms of dendritic transport, using Drosophila as a model system. Our data suggest that dendritic targeting systems in Drosophila and mammals are evolutionarily conserved, since mammalian cargoes are moved into appropriate domains in Drosophila. In a genetic screen for mutants that mislocalize the dendritic marker human transferrin receptor (hTfR), we found that kinesin heavy chain (KHC) may function as a dendritic motor. Our analysis of dendritic and axonal phenotypes of KHC loss-of-function clones revealed a role for KHC in maintaining polarity of neurons, as well as ensuring proper axonal outgrowth. In addition we identified adenomatous polyposis coli 1 (APC1) as an interaction partner of KHC in controlling directed transport and modulating kinesin function in neurons.