Inhibition of ADAMTS-4 Expression in Olfactory Ensheathing Cells Enhances Recovery after Transplantation within Spinal Cord Injury.

Spinal cord injury (SCI) induces permanent loss of sensitive and motor functions below the injury level. To date, a wide variety of cells has been used as biotherapies to cure SCI in different animal paradigms. Specifically, olfactory ensheathing cells (OECs) is one of the most promising. Indeed, OECs have been shown to enhance recovery in many animal studies. Moreover, OECs transplantation has been applied to a paraplegic patient and have shown beneficial effects. However, it has been reported that the significant level of recovery varies among different patients. Therefore, it is of primary importance to enhance the regenerative efficiency of OECs for better translations. Recently, it has been shown that inhibiting ADAMTS4 expression in glial cells in vitro increases their synthesis of neurotrophic factors. We hypothesized that the expression of neurotrophic factors secreted by OECs can be increased by the deletion of ADAMTS4. Taking advantage of ADAMTS4-/- mouse line, we produce ADAMTS4 deficient primary OEC cultures and then we investigated their regenerative potential after SCI. By using quantitative polymerase chain reaction, bioluminescence imaging, measurement of locomotor activity, electrophysiological studies, and immunohistochemistry, our results show that ADAMTS4-/- olfactory bulb OEC (bOECs) primary cultures upregulate their trophic factor expression in vitro, and that the transplantation of ADAMTS4-/- bOECs in a severe SCI model increases functional recovery and tissue repair in vivo. Altogether, our study reveals, for the first time, that primary bOEC cultures transplantation can be potentialized by inhibition of the expression of ADAMTS4.

Replicative senescence of human dermal fibroblasts affects structural and functional aspects of the Golgi apparatus.

It is well recognized that the world population is ageing rapidly. Therefore, it is important to understand ageing processes at the cellular and molecular levels to predict the onset of age-related diseases and prevent them. Recent research has focused on the identification of ageing biomarkers, including those associated with the properties of the Golgi apparatus. In this context, Golgi-mediated glycosylation of proteins has been well characterized. Additionally, other studies show that the secretion of many compounds, including pro-inflammatory cytokines and extracellular matrix-degrading enzymes, is modified during ageing, resulting in physical and functional skin degradation. Since the Golgi apparatus is a central organelle of the secretory pathway, we investigated its structural organization in senescent primary human dermal fibroblasts using confocal and electron microscopy. In addition, we monitored the expression of Golgi-related genes in the same cells. Our data showed a marked alteration in the Golgi morphology during replicative senescence. In contrast to its small and compact structure in non-senescent cells, the Golgi apparatus exhibited a large and expanded morphology in senescent fibroblasts. Our data also demonstrated that the expression of many genes related to Golgi structural integrity and function was significantly modified in senescent cells, suggesting a relationship between Golgi apparatus function and ageing.