Stimulating Endogenous Stem Cells as a therapy for Degenerative Muscle Disease: Project making significant progress
Research Advances Identifying stem cells In a paper1 published in the Proceedings of the national academy of Sciences, the team of Dr. Marazzi and Dr. Sassoon (Université Pierre et Marie Curie, France) in collaboration with Dr. Relaix (Université Pierre et Marie Curie, France) report the development of a model that allows them to detect cells expressing a gene known as PW1. The teams were able to easily identify stem cells in every tissue examined, including the brain and skin. This mouse model demonstrates that PW1 serves as an invaluable marker for competent self-renewing adult stem cells and promises application in fundamental research and therapeutic development, as self renewal is a critical characteristic of all stem cells. Understanding muscle formation and maintenance The balance between muscle stem cell self-renewal and differentiation is crucial during early muscle formation (myogenesis) from progenitors. Dr. Relaix’s team (Université Pierre et Marie Curie, France) has shown in a study2 published in the high impact ‘Developmental Cell’ journal that the neural crest cells (NCC), a cell population that gives rise to different cell lineages, is involved in regulating the commitment of skeletal muscle progenitor cells to myogenesis. The interaction between the cell types controls survival of the muscle progenitor cells and sustains them in an undifferentiated state. Essentially, understanding muscle development is pivotal to muscle regenerative medicine3. Boost for therapeutic applications of mesoangioblasts Mesoangioblasts are a population of blood vessel-associated stem cells that have been shown to contribute to muscle repair when transplanted in dystrophic mice, dogs and are now in clinical trials in humans. A study by Dr. Brunelli’s team4 showed that the protein necdin is able to accelerate and enhance myogenic differentiation of endogenous or transplanted mesoangioblasts and to increase cell survival, thus leading to a more efficient reconstitution of the dystrophic muscle. In particular, they found that necdin acts through a transcriptional regulation of myogenin, in cooperation with a transcription factor called MyoD. Cell junctions as therapeutic target As an extension of the blood vessel work, Prof. Dejana (IFOM, Italy) has studied circulating endothelial progenitors (key maintaining cells of blood vessel integrity) and the mechanisms that induce their mobilization and migration to damaged areas. Published in PLOS One she has demonstrated that the absence an adhesion molecule of tight junctions (named JAM-A), does not modify angiogenesis5, offering critical insight ensuring efficient nutrient supply to growing tissues. A 2-step model to access target genes Dr. Puri’s group (Dulbecco Telethon Institute, Italy) unravelled the interactions between MyoD, and chromatin in undifferentiated muscle cells6. Indeed, the conformation of chromatin in these cells is such that MyoD is unable to access the specific site of the chromatin to allow genes to be transcribed into proteins. Their findings revealed that a complex, allows MyoD to binds to the chromatin at a specific site. A signalling cascade then remodel the chromatin to allow the transcription machinery to access the target gene and initiate differentiation. This evidence explains the mechanism by which tissue-specific transcription factors access the chromatin at specific site previously silenced and impact the balance between stem cells and their differentiated progeny. New mechanism controlling inflammation and tissue repair After injury of the skeletal muscle, specific immune cells provide the first signals to activate ‘satellite’ cells as part of the normal inflammation process, which should be regulated in order for the muscle to heal properly, otherwise large scar tissue forms. This phenomenom involves a transition of the immune cells from a proinflammatory state to an antiinflammatory one. Prof. Muñoz-Cánoves’ team (Pompeu Fabra University, Spain) provided evidence7 for a new role for a specific protein named MKP-1 in regulating this transition and the resolution of inflammation during muscle regeneration. The team also showed that MKP-1 is not necessary for satellite cell repair. Prof. Muñoz-Cánoves’ team propose a model whereby induction of specific factors in proinflamatory cells, stimulates a signal cascade in the antiinflammatory immune cells. This offers new avenues for treating inflammatory myopathies 8, 9,10, 11. Sustaining the muscle stem cell pool: Nitric Oxide in the Clinic The muscle stem cell, becomes depleted as several rounds of regeneration occur during repetitive-acute and chronic damages such as in muscular dystrophy. Prof. Clementi’s team (University of Milano, Italy) in collaboration with Dr. Brunelli (San Raffaele Scientific Institute, Italy), has clearly demonstrated, that the anti oxidant, nitric oxide stimulates muscle stem cell self renewal in such a way that it prevents the exhaustion of their reserve pool. These results12, published in ‘Stem Cells’, led to the identification of molsidomine, a nitric oxide releasing drug approved for use in humans, as a potential therapeutic for muscular dystrophies. Prof. Clementi has shown that NCX 320, a compound releasing both ibuprofen and the antioxidant nitric oxide, had significant therapeutic effects in a pre-clinical model of muscular dystrophy13. Little is known about the oxidative changes triggered by muscle injury and their role in the regeneration process. ROS (reactive oxygen species) generation occurs in the damaged muscle soon after injury. Dr. Brunelli found out that soon after, an antioxidant response is triggered promoting muscle regeneration14 providing mechanistic insight to Prof. Clementi’s pre-clinical work. Importantly, and as an extension of this work, Prof. Clementi has also reported the successful outcome of a phase IIa clinical trial, which enrolled patients suffering from Duchenne, Becker and Limb Girdle dystrophies that were treated with a combination of the nitric oxide/ibuprofen15 opening the way for effective therapeutic application. References 1- Besson V, Smeriglio P, Wegener A, Relaix F, Nait Oumesmar B, Sassoon DA, Marazzi G. PW1 gene/paternally expressed gene 3 (PW1/Peg3) identifies multiple adult stem and progenitor cell populations. Proc Natl Acad Sci U S A. 2011 Jul 12;108(28):11470-5. 2- Van Ho AT, Hayashi S, Bröhl D, Auradé F, Rattenbach R, Relaix F. Neural crest cell lineage restricts skeletal muscle progenitor cell differentiation through Neuregulin1-ErbB3 signaling. Dev Cell. 2011 Aug 16;21(2):273-87. 3- Hayashi S, Rocancourt D, Buckingham M, Relaix F. Lack of in vivo functional compensation between Pax family groups II and III in rodents. Mol Biol Evol. 2011 Oct;28(10):2787-98. 4- Pessina P, Conti V, Tonlorenzi R, Touvier T, Meneveri R, Cossu G, Brunelli S. Necdin enhances muscle reconstitution of dystrophic muscle by vessel-associated progenitors, by promoting cell survival and myogenic differentiation. Cell Death and Differentiation. 2011 Dec 5- Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E. Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression. PLoS One. 2011;6(6) 6- Forcales SV, Albini S, Giordani L, Malecova B, Cignolo L, Chernov A, Coutinho P, Saccone V, Consalvi S, Williams R, Wang K, Wu Z, Baranovskaya S, Miller A, Dilworth FJ, Puri PL. Signal-dependent incorporation of MyoD-BAF60c into Brg1-based SWI/SNF chromatin-remodelling complex. EMBO J. 2011 Nov 8. 7- Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardí M, Caelles C, Serrano AL, Muñoz-Cánoves P. p38/MKP-1–regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol. 2011 Oct 17;195(2):307-22. 8- Muñoz-Cánoves P. http://jcb.rupress.org/site/biobytes/biobytes_oct_17_2011.mp3(si apre in una nuova finestra). 2011 Oct 17. 9- Serrano AL, Mann CJ, Vidal B, Ardite E, Perdiguero E, Muñoz-Cánoves P. Cellular and Molecular Mechanisms Regulating Fibrosis in Skeletal Muscle Repair and Disease. Current Topics in Developmental Biology. 2011 Mar. 10- Sousa-Victor P, Muñoz-Cánoves P, Perdiguero E. Regulation of skeletal muscle stem cells through epigenetic mechanisms. Toxicol Mech Methods. 2011 May;21(4):334-42. Review. 11- Mann CJ, Perdiguero E, Kharraz Y, Aguilar S, Pessina P, Serrano AL, Muñoz-Cánoves P. Aberrant repair and fibrosis development in skeletal muscle. Skelet Muscle. 2011 May 4;1(1):21. 12- Buono R, Vantaggiato C, Pisa V, Azzoni E, Bassi MT, Brunelli S, Sciorati C, Clementi E. Nitric Oxide Sustains Long Term Skeletal Muscle Regeneration by Promoting satellite cells self-renewal via Vangl2 and cyclic GMP. Stem Cells. 2011. 13- Sciorati C, Miglietta D, Buono R, Pisa V, Cattaneo D, Azzoni E, Brunelli S, Clementi E. A dual acting compound releasing nitric oxide (NO) and ibuprofen, NCX 320, shows significant therapeutic effects in a mouse model of muscular dystrophy. Pharmacol Res. 2011 Sep;64(3):210-7. 14- Vezzoli M, Castellani P, Corna G, Castiglioni A, Bosurgi L, Monno A, Brunelli S, Manfredi AA, Rubartelli A, Rovere-Querini P. High-mobility group box 1 release and redox regulation accompany regeneration and remodeling of skeletal muscle. Antioxid Redox Signal. 2011 Oct 15;15(8):2161-74. 15- Grazia D'Angelo M, Gandossini S, Martinelli Boneschi F, Sciorati C, Bonato S, Brighina E, Pietro Comi G, Turconi AC, Magri F, Stefanoni G, Brunelli S, Baldelli S, Bresolin N, Cattaneo D, Clementi E. Nitric oxide donor and anti inflammatory drugs: a pilot safety study in muscular dystrophies. Clinical Neuropharmacology. 2011 For more information: EndoStem: www.endostem.eu