Fractones: proteoglycan matrix for growth factor activity in health and disease

Abstract

Growth factors, cytokines and chemokines are proteins that influence cell proliferation, differentiation, migration, apoptosis and other biological determinants that determine cell fate and cell functions, ultimately the phenomena of generation, regeneration, and degeneration throughout life. Most of these molecules diffuse throughout biological fluids and bind heparin. In vivo they require heparan sulfate proteoglycans (HSPG) located in the extracellular matrix (ECM) to target their cell‐surface receptors and ultimately induce specific biological effects. We have characterized by immunohistochemistry and electron microscopy a new structure found in some parts of the extracellular space as part of the ECM that we named fractones. Fractones are chemically similar to basement membranes and consist of laminin isoforms, collagen‐IV, nidogen and HSPG. However, fractones and basement membranes differ by their location. Fractones reside in the parenchyma of tissues and organs and are visualized as particles by light microscopy whereas they often display a fractal ultrastructure (a reference to their name). In contrast, basement membranes are located as sheaths at the connective tissue/parenchyma interface and in between the layers of the vascular wall. We have shown that fractone‐associated heparan sulfates bind, concentrate, and activate the growth factors FGF‐2, BMP‐4 and BMP‐7 to regulate stem cell proliferation in the neurogenic zone of the adult brain. We have also found fractones are abundantly expressed throughout mammalian development and distributed in a manner that reflects morphogenesis. Fractones were found in all animals that we investigated including vertebrates (human, mouse and rats) and invertebrates (cnidarians, sponges, copepods, decapodes, insects). HSPG are highly dynamic molecules formed by post‐translational processes in both the Golgi apparatus, and in the ECM where extracellular enzymes are also secreted. Our results strongly suggest that fractones are essential chemicals for constructing and maintaining biological structures. We are currently elaborating the model of tissue explants, i.e. miniature fragments of organs to study growth factors/fractone interactions that will ultimately provide insights into the mechanisms that control cell fate in a near‐physiological context. We anticipate that the model explants originating from physiological animals and from animal disease models will revolutionize our understanding of molecular interactions between proteoglycans and their ligands through tissues and organs and throughout life. This research will provide the basics for new paradigms that orchestrate biological structures and functions in health and disease. We are interested in establishing methods to identify specific carbohydrate sequences in the ECM structures that bind signaling proteins. This may allow elucidation of a signaling code used by tissues for growth and maintenance. Establishment of such a code would allow for discovery of disease.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.