Heat Shock Proteins in Multiple Sclerosis Pathogenesis: Friend or Foe?

Multiple Sclerosis is a complex chronic inflammatory, neurodegenerative disease conditioned by genetic, epigenetic and environmental factors. Main pathological features of MS include areas of focal demyelination of white matter characterized by gliosis, neuron and oligodendrocyte loss. Neurodegenerative as well as immune-mediated processes play a role in the pathogenesis of this disease. One of these immunogenic factors could be represented by the heat shock proteins. HSP exhibit cytoprotective and cytostimulatory effects due to their molecular chaperones role, in many brain model misfolding diseases such as Alzheimer’s and Parkinson’s diseases, whereas still no unambiguous results have been reported for autoimmune disorders of the central nervous system such as Multiple Sclerosis. Actually, either positive or negative HSP role seems to depend on HSP family and on their intracellular or extracellular localization. It will be interesting to study drug treatment which overexpress or inhibit HSP production in order to gain much more information about the role of the HSP in this disease

Extracellular Hsp70 Enhances Mesoangioblast Migration via an Autocrine Signaling Pathway

Mouse mesoangioblasts are vessel-associated progenitor stem cells endowed with the ability of multipotent mesoderm differentiation. Therefore, they represent a promising tool in the regeneration of injured tissues. Several studies have demonstrated that homing of mesoangioblasts into blood and injured tissues are mainly controlled by cytokines/chemokines and other inflammatory factors. However, little is known about the molecular mechanisms regulating their ability to traverse the extracellular matrix (ECM). Here, we demonstrate that membrane vesicles released by mesoangioblasts contain Hsp70, and that the released Hsp70 is able to interact by an autocrine mechanism with Toll-like receptor 4 (TLR4) and CD91 to stimulate migration. We further demonstrate that Hsp70 has a positive role in regulating matrix metalloproteinase 2 (MMP2) and MMP9 expression and that MMP2 has a more pronounced effect on cell migration, as compared to MMP9. In addition, the analysis of the intracellular pathways implicated in Hsp70 regulated signal transduction showed the involvement of both PI3K/AKT and NF-κB. Taken together, our findings present a paradigm shift in our understanding of the molecular mechanisms that regulate mesoangioblast stem cells ability to traverse the extracellular matrix (ECM)