Siginifiant progress in stimulating endogenous stem cells for tissue repair made by Endostem project
Paris (France), October 2013 – The EndoStem consortium (www.endostem.eu) 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, has generated a number of advances, with an exciting year of significant research and development advances for treating muscular dystrophies by targeting endogenous stem cells. Siginifiant progress in stimulating endogenous stem cells for tissue repair made While the clinical trials of new therapeutics and the preclinical development of the prioritised molecule ‘cripto’ are progressing for treating Muscular Dystrophy, the Endostem partnership has also made significant advances in deciphering the complex and tightly regulated interactions between inflammatory cells recruited into the injured tissue and myogenic precursor cells, as part of the regeneration of injured muscle, resulting in publications in several high impact journals including Cell, Cell Metabolism, Development, and Nature. These represent critical and pivotal insights, for muscular diseases and for the wide range of age related and degenerative diseases that affect our society; the mechanisms of stem cell control and immune system modulation in a damaged tissue are similar between tissues and therefore the applicability of our insights are enhanced. This has been specifically illustrated in our project recently through focuses on cardiac muscle stem cells. In Muscular Dystrophy, the heart is also impacted and in addition to targeting the skeletal muscle itself, focus also needs to be placed on the patient as a whole and total body repair. The ramifications are obvious, knowledge on treating cardiac related effects in Muscular Dystrophy have an automatic translation to more common cardiac related diseases, where stem cell activation, scarring and fibrosis and immune modulation are critical for restoration of tissue functionality. By successfully ‘repositioning’ the concept and application, this opens the flood gates to development and application of not only our approaches, but those of our peers and colleagues around the globe, all aimed towards generating new knowledge, benefitting society, and alleviating disease. Major insights obtained include: 1) Confirmation by the group of Sassoon and Marazzi, that the previously identified PW1 interstitial cells (a newly identified stem cell that can be identified via the expression of the PW1 marker) and the muscle satellite cells are distinct muscle forming progenitors, and that both the juvenile and adult PW1 interstitial cells can have multiple cell fate potentials. Results also indicated that PW1 expression defines all muscle resident stem/progenitor cells. 2) Detail of the immune microenvironment in damaged tissue and suitable approaches to influence this to enhance tissue repair has been revealed by the teams of B. Chazaud, and C. Combadiere. To recap, following damage the tissue is infiltrated by a collection of immune cells whose interplay protect against foreign infection, and then stimulate tissue repair. In larger tissue damage, the body also has the mechanism of filling the ‘gap’ with scar tissue to maintain integrity, but not functionality. By understanding and modulating this environment, protection can be maintained, with the additional aim to slow scarring and permit restoration of tissue functionality. B. Chazaud’s team identified a master regulator of energy homeostasis in the immune cells, while C. Combadiere’s team revealed that modulating cell surface molecules that are linked to cell movement and therefore infiltration can positively impact the tissue restorative process. Modulating the rate of cell mobilization during the ‘restoration’ phase could contribute to recovery from a range of insults while maintaining effective host defense. 3) Previous work by the team of PL Puri, has established the existence of dystrophin-nitric oxide (NO) signaling to histone deacetylases (HDACs) that is deregulated in dystrophic muscles. As such, pharmacological interventions that target HDACs (that is, HDAC inhibitors) are of potential therapeutic interest for the treatment of muscular dystrophies. The HDAC inhibitor is about to enter clinical trial for treating Muscular Dystrophy, which has been complemented by results of this team revealing that long-term (3.5 months) exposure of 1.5-month-old Muscular Dystrophy mice to optimal concentrations of givinostat promoted the formation of larger muscles, reduced inflammatory infiltrate and scarring, leading to an overall improvement of muscle functionality and endurance. These findings provided the preclinical basis for the immediate translation of givinostat into clinical studies with DMD patients. To augment the application and delivery of these therapeutics (at present taken via a pill) the team of J. Hubbell has developed a facile method to generate combined delivery systems with the ibuprofen in which the combination can be tailored to different sizes and structures which is significant and important to control the life of the pharmaceutial as well as its distribution to the target tissue. For example the linear ‘worm-like’ combinations generated are known to have extremely long circulation time as well as high stability, thus permitting a better delivery of the therapy. 4) Defects in Nitric Oxide (NO) generation is a key pathogenic event in muscular dystrophies, thus NO donors have been explored as new therapeutics for this disease. The critical role of Nitric Oxide (NO) synthesis in muscle regeneration as a key messenger in regulating myogenic precursor cell fate and the inflammatory response in muscle damage/regeneration has been demonstrated by the team of S. Brunelli thus permitting a fine tuning of the therapy presently in clinical trial to augment their effectiveness in healing muscle damage after acute or prolonged injury. The possibility to modulate finely the inflammatory response is of pivotal importance in chronic degenerative diseases of the skeletal muscle, in which a general non-specific anti-inflammatory activity could be more detrimental than beneficial. It is thus extremely important in therapeutic perspective as it interconnects direct effects of NO on muscle with indirect effects via inflammation. Additionally changes in heart metabolism occur in Muscular Dystrophy patients; the team of E. Clementi has reported that the combination Nitric Oxide-Ibuprofen therapeutic strategy is effective in balancing altered heart regulation. Altered cardiac activity can result in an impaired regulation of blood flow during exercise with ensuing low tissue perfusion and ischaemia, further compounding the suffering of the patients; it is therefore essential that both therapies designed for the primary manifestation of the disease (muscle loss), also positively impact secondary manifestations, such as the heart, to provide a total disease alleviation. 5) Endogenous cardiac stem cells (eCSC) can be identified and stimulated to repair and regenerate damaged heart tissue following myocardial damage which can cause acute heart failure. This represents a seminal work by the team of B. Nadal Ginard, and was published in the renouned journal, Cell. Given the advances indicated above in modulation of the inflamed tissue environment, and the mechanisms of action of drugs presently in clinical trial matched with a tailored drug delivery system, the potential to optimise and stimulate endogenous stem cells to repair the damage is close to becoming a reality. This is a pivotal moment as it is generally accepted that, in healthy adult tissue, most stem cells are quiescent and if they cycle they do so very slowly, providing just enough transient amplifying cells to maintain tissue homeostasis. In contrast, the quiescent stem cells in response to injury are rapidly activated, multiply, and differentiate to replace the cells lost, but this is not sufficient to repair large tissue damage, and therefore enhanced stem cell stimulating approaches being developed by us, offer real future potential.
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