Endostem progressing in developing novel stem cell stimulating therapeutics
The EndoStem consortium (http://www.endostem.eu/(opens in new window)) a large scale scientific collaboration coordinated by Dr. David Sassoon (UPMC/Inserm, Paris, France), and co-financed by the European Commission via the 7th Framework Programme, is making significant advances in the development of novel therapies that target resident stem cells and encourage them to repair damaged tissue in situ, with a specific focus on muscle diseases. Passing the project mid-way point (nearly 36 months since the start), in addition to increases in its industrial participation and clinical trial outputs, the project is identifying key molecular mechanisms associated with the inflammatory, scar forming state and specific molecules that can be used to modify this and stimulate the endogenous stem cells. These common mechanisms will provide essential information on generating a portfolio of drugs for treating many degenerative and age related diseases as well as treating injuries, which prevent an active life and continued economic contribution. Modulation of the inflammatory state The teams of Marco Bianchi (HMGBiotech), and Christophe Combadiere (UPMC) have made significant advances in understanding the precise micro molecular and cellular controls that occur in the localised sites of tissue damage. Marco’s team has found that a key protein that is activated following tissue damage has very precise control mechanisms, very similar to a fine tuning switch which instructs what the normal immune cells should do. Published in the Journal of Experimental Medicine, this specific protein, named HMGB1 is highly sensitive to the surrounding oxidation levels which, when altered, can orchestrate the inflammatory environment by recruiting specific cells or inducing factor secretion; this ties in with pivotal clinical work in which modulation of the oxidative environment as part of inducing tissue repair in human tissues. Work on the double-edged nature of the inflammatory response in tissue damage was also assessed by the team of Christophe. His work has identified that in the context of severe cardiac muscle damage excessive inflammation is detrimental to the tissue repair response; which in effect can be controlled and modulated; this modulation was possible by sequestering factors that attract the damaging immune cells using a specific decoy. This insight provides critical insight on finding targets for therapeutic intervention, which can fine tune and balance the protective versus detrimental immune response. The critical aspect of this work, is that the mechanisms of immune response to tissue damage are very common across tissues, thereby developing targets and therapeutics for one tissue will likely lead to a very broad application. Maintaining the resident cell population that repairs the tissue The team of Silvia Brunelli from Milan (HSR), recently published work in PLOSOne characterising the mechanism of action of one of the key proteins involved in the survival of muscle repairing cells, called Necdin. This protein is active throughout all human life and responsible for regeneration of the muscle fibres and Silvia’s team has revealed that it exerts this potential by activating molecular pathways which modulate a cell killing protein. While cell death and cell turnover are common features of everyday cell life, in the context of repairing tissue, this normal process needs to be controlled to ensure that damaged tissue can properly repair. Along similar lines, the teams of David Sassoon and Giovanna Marazzi (UPMC/Inserm) have characterised the action of a key gene in the muscle cell itself. This gene, which is responsible for repairing the DNA and maintaining its integrity, when disactivated, results in stem cell dysfunction and accelerated ageing. Maintenance of DNA integrity and its decrease as we age has been known for sometime to be intrinsically linked. The sequences of DNA at the ends of chromosomes act similarly to the taped ends of shoelaces; when present the shoe lace stays in tact, but when absent the laces become quickly frayed and non-functional. Published in EMBO Molecular Medicine, David and Giovanna have revealed that when this specific gene is absent, or if just one of the two copies of the gene is absent, early ageing can be induced and the capacity of the muscle stem cells to repair tissue is dramatically reduced. The impact of the work is significant in that it has generated a readily available model for studying ageing and developing therapeutics while revealing the intrinsic relationship between resident stem cells, their fine molecular control and maintenance of tissue integrity. The poor muscle repair noted in mice carrying just one good copy of the gene (instead of the normal two copies) does not appear until the muscle is challenged to regenerate twice. This observation has impact on the mechanisms underlying degenerative muscle diseases in which the tissue is continually challenged to regenerate. Advances in biotherapeutic development One of the projects key candidates for therapeutic development is steadily advancing; the molecule, named ‘Cripto’ has been revealed to regulate muscle cell generation. Published by the team of Gabriella Minchiotti in the prestigious journal ‘Proceedings of the National Academy of Sciences USA’, her team has demonstrated that a protein that has a key role in the early stages of development also has a key role during adult life. In adult life, so far it has not been identified as playing a key role, however Gabriella has demonstrated that in quiescent or non active muscle stem cells there is no expression, however when the stem cells start to regenerate tissue Cripto expression increases and that this enables the expansion of the resident stem cells mainly by disactivating a cell growth blocker. This mechanism of action is being further studied to better understand the fine interplay and subtle differences of Cripto activity between muscle stem cell control in a normal situation versus a damaged situation and as such generate a tailored therapeutic approach; simultaneously effort is being focused on identifying the necessary steps for therapeutic translation of this protein.
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