RGTA® or ReGeneraTing Agents mimic heparan sulfate in regenerative medicine: from concept to curing patients

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is highlighted by numerous pathologies and situations of acute and chronic injury associated with dysregulation or destruction of ECM components. Heparan sulfate (HS) is a key component of the ECM, where it fulfils important functions associated with tissue homeostasis. Its degradation following tissue injury disrupts this delicate equilibrium and may impair the wound healing process. ReGeneraTing Agents (RGTA®s) are polysaccharides specifically designed to replace degraded HS in injured tissues. The unique properties of RGTA® (resistance to degradation, binding and protection of ECM structural and signaling proteins, like HS) permit the reconstruction of the ECM, restoring both structural and biochemical functions to this essential substrate, and facilitating the processes of tissue repair and regeneration. Here, we review 25 years of research surrounding this HS mimic, supporting the mode of action, pre-clinical studies and therapeutic efficacy of RGTA® in the clinic, and discuss the potential of RGTA® in new branches of regenerative medicine

Regenerating agents (RGTAs): a new therapeutic approach

RGTAs, or ReGeneraTing Agents constitute a new class of medicinal substance that enhance both speed and quality of tissue healing and leading in some case to a real tissue regenerating process. RGTAs consist of chemically engineered polymers adapted to interact with and protect against proteolytic degradation of cellular signaling proteins known as growth factors, cytokines, interleukins, colony stimulating factors, chemokines, neurotrophic factors etc. Indeed almost all these proteins of cellular communication are naturally stored in the extra cellular matrix interacting specifically with the heparan sulfates or HS. After tissue injury of any cause, cells die liberating glycanases and proteases inducing first HS degradation then liberation of the cytokines which in turn are susceptible to degradation as they are no longer protected. By replacing the natural HS, RGTAs will protect cytokines from proteolyses as they are liberated from the matrix compartment matter in the wound. This spatio-temporal selective protection of cytokines results in a preservation of the natural endogenous signaling of a tissue and is reflected by spectacular tissue regeneration or by a very greatly improved tissue repair. These observations indicate that mammals have an unexpected ability to regenerate and that RGTA helps to reveal this capacity. The aim of OTR3 is to develop RGTA into a drug to treat specific tissue lesions

Interactions of FGFs with target cells.

International audienceGrowth factors play a key role in cellular communication, a necessary step for the development of pluricellular organisms. The fibroblast growth factors (FGF) are among these polypeptides and have seven known members: FGF 1 to FGF 7 which are also known as acidic FGF, basic FGF, translation products of oncogenes hst, int 2, FGF 5, FGF 6 and FGF 7 or keratinocyte growth factor (KGF) respectively [1]. The best known and the most abundant in normal adult tissues are acidic and basic FGFs, or FGF 1 and 2 respectively, which have been subjected to extensive studies both in vitro and in vivo. These two factors have almost ubiquitous distribution and a wide spectrum of biological activity including action on cellular proliferation and differentiation, as well as neurotrophic and angiogenic properties [1]. These different activities are induced by triggering specific receptors present at the surface of the target cell. Following this interaction, the FGF-receptor complexes are internalized and activate intracellular pathways. An important effort of investigations has been produced to characterize these receptors and intracellular pathways. It is the purpose of this review to present this work which will focus on FGFs 1 and 2. The existence of two classes of interactions has been reported as early as 1987 [52, 53, 54] suggesting the presence of high and low affinity receptors for FGFs

Extracellular Matrix Covered Biomaterials for Human Endothelial Cell Growth

The aim of this study is to optimize conditions for growing endothelial cells on vascular biomaterials. Bovine cornea endothelial cells (BCEC), stimulated by basic Fibroblast Growth Factor (bFGF) secrete an extracellular matrix (ECM) similar to the Descemet membrane produced in vivo by these cells. This ECM, obtained by removing BCEC with an hypotonic shock can be used as a substratum for other endothelial cell growth. Human endothelial cells (HEC) were purified from omentum that was digested with a solution of collagenase-dispase, then filtered through nylon meshes. The cells were further purified by centrifugation onto a Percoll gradient. A comparative study on the attachment and growth of HEC on various coatings (laminin, poly-L-lysine, fibronectin or ECM) indicates that ECM is the most performing substratum. The quality of this endothelium was confirmed by the presence of factor VIII, and MHC class I and the absence of class II antigens. </jats:p