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ICNMD XIII 13Th International Congress on Neuromuscular ICNMD XIII 13th International congress on Neuromuscular Diseases Nice, France July 5-10, 2014 Poster Sessions Abstract Books Journal of Neuromuscular Diseases 1 (2014) S83–S403 S83 DOI 10.3233/JND-149002 IOS Press Abstracts PF1 These unexpected results were confi rmed in vitro in cultured myoblasts. Accordingly MyoD and MyoG expressions were not altered by Srf loss. PS1-1 / #138 - that SC late differentiation and fi ber growth were Theme: 1.1 - Basic sciences in NMD: Muscle homeostasis / Muscle altered in vivo and in vitro. regeneration Further characterization of SC cell behaviour (self- renewal, motility, survival...) will be presented. In ad- Role of Serum response factor in dition, we performed transcriptomic studies and muscular satellite cells identifi ed the set of genes whose expressions are al- tered by Srf loss in proliferating and differentiating Voahangy Randrianarison-Huetz, Aikaterini myoblasts. Genes identifi ed in this screen will aid de- Papaefthymiou, Laura Collard, Ulduz Faradova, ciphering the underlying molecular mechanism. Athanassia Sotiropoulos Genetics and Development, Institut Cochin, Paris, France PS1-2 / #247 In the muscular system, thetranscription factor Srf Theme: 1.1 - Basic sciences in NMD: Muscle homeostasis / Muscle (Serum response factor) controls the expression of a regeneration wide range of genes including those involved in pro- liferation (immediate early genes) and myogenic dif- Sdf-1 promotes BMSCs participation in ferentiation (MyoD, a-actin). Indeed, inhibition of Srf regeneration of Pax7-/- mouse skeletal in cultured myogenic cell lines C2C12 was shown to impede myoblast’s proliferation and differentiation muscles into myotubes. However data are lacking regarding Kamil Kowalski, Maria Ciemerych, Edyta Brzóska the role of Srf in muscle stem cells behavior in vivo. Cytology, University of Warsaw, Faculty of Biology, For this purpose, we generated Pax7-CreERT2;Srffl x/fl x Warsaw, Poland mice in which Srf loss is induced in satellite cells (SC) after tamoxifen injection. In parallel we conducted ex The skeletal muscle is characterized by an unique vivo cultures of primary myoblasts expressing or not ability to reconstruct its structure and regain function- Srf (Srffl x/fl x myoblasts transduced with adenoviral vec- ality after the injury. Regeneration is mediated by the tors expressing the recombinase Cre, and Pax7- muscle specifi c stem cells, i.e. satellite cells. Howev- CreERT2;Srffl x/fl x;Pax7-GFP sorted cells) to further er, in case of extensive damage, satellite cells cannot study the cellular and molecular processes involved. fully reconstruct muscle architecture. In such case We demonstrated : other stem cell populations can serve as a potential - that Srf is very faintly expressed in quiescent SC source of myogenic cells. Previously, it was shown while prominently in activated/proliferative SC. that bone marrow stem cells (BMSCs) manifest the - that Srf deletion in SC did not alter their number ability to follow the myogenic program in vitro. How- nor their quiescent state suggesting that Srf is not cru- ever, the process of BMSC engraftment into injured cial for the maintenance of SC quiescence in steady muscle is ineffi cient and only few percent of new state conditions. In contrast, following cardiotoxin muscle fi bers is formed with the participation of BM- CTX-induced muscle regeneration or overload-in- SCs. In our study we focus at chemokine Sdf-1 (stro- duced hypertrophy, Srf loss in SC strongly affected mal derived factor-1) which is one of the crucial muscle regeneration and muscle growth indicating a factors participating in the regulation of cells migra- contribution of Srf activity to SC fate in stress tion during development and regeneration. Previous- conditions. ly, we showed that Sdf-1 improves the regeneration of - that upon injury or overload, SC proliferation and skeletal muscles. In the present study we take early differentiation were not affected by Srf loss. advantage of mice lacking Pax7 transcription factor ISSN 2214-3599/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. S84 Abstracts (Pax7-/-) to test whether stem cells other than satellite PS1-3 / #303 cells could participate in the reconstruction of skeletal Theme: 1.1 - Basic sciences in NMD: Muscle homeostasis / Muscle muscle. Skeletal muscles of these mice are severely regeneration depleted of satellite cells and for this reason cannot effi ciently regenerate. We used Sdf-1 to impact at the Control of the fate of human muscle stem stem cells mobilization and G-CSF to increase the number of mobilized cells. cell by modulation of the in vitro Our results show that regenerating, Sdf-1 treated microenvironment Pax7-/- muscles were characterized by increased Claire Monge1, Nicholas DiStasio1, Anne Bigot2, weight, increased expression of muscle proteins and Vincent Mouly2, Catherine Picart1 lower fi brosis, as compared with control muscles. 1Interface between material and biological matter, This effect can be explained by the infi ltration of re- LMGP, Grenoble, France generating muscle with mononucleated cells express- 2Thérapie des maladies du muscle strié, Institut de ing Cxcr4 and Cd34. Next, we use G-CSF to increase Myologie, Paris, France the number of Sdf-1 mobilized cells. After such treat- ment we observed increased number of Cd34+and Several therapeutic approaches are currently devel- Cxcr4+ cells in regenerating Pax7-/- muscles as com- oped for the treatment of the loss of skeletal muscle pared with control ones. Since, the number of satellite tissue function. Cell therapy, which consists in the cells did not change after Sdf-1 administration we isolation, in vitro expansion and intramuscular trans- suggested that Cd34+and Cxcr4+ cells were mobi- plantation of muscle progenitor cells (satellite cells) lized from the bone marrow. Importantly, more new isolated from the patient or from a healthy donor, is myofi bers was formed in the muscles of Pax7-/- mice limited by the amount of isolated cells and the geno- injected with G-CSF and Sdf-1. We suggested, that in typic shift that the cells undergo when kept on typical the absence of satellite cells Cd34+ and Cxcr4+cells, culture dishes. mobilized from the bone marrow, can effi ciently par- We are currently developing a biomaterial adapted ticipated in the skeletal muscle reconstruction. to the culture of satellite cells. Our aim is to reconsti- tute in vitro a cellular environment capable to provide satellite cells specifi c signals that mimic their natural niche. There are now several experimental evidences that muscle cells in their native microenvironments are sensitive to mechanical, biochemical and topo- graphical cues. The satellite cell is indeed confi ned in Fig. 1. Miniaturized culture plateform for the screening of conditions for the culture of satellite cells. Rigidity, biochemistry and topography can be modulated separately or combined together. The rigidity ( ) is varied by chemical cross-linking of the PEM fi lm. The biochemistry ( ) of the substrate is modulated by grafting of peptide or incorporation of growth factors. The topography ( ) is provided by microsctucturation of the underlying sub- stracte. Abstracts S85 its niche and surrounded by extracellular matrix using muscle biopsies obtained from healthy donors (ECM) components as laminin or collagen and bioac- of various ages, or presenting with Duchenne muscu- tive molecules as growth factors. The development of lar dystrophy, and using biopsies from normal and innovative biomaterials is then of great interest in or- mdx mice of various ages. In Human, we observed a der to overcome the limitations faced in the in vitro trend toward a decrease then a stabilization in the pro- culture of satellite cells. portion of ALDH+ cells with age, both sub-popula- By the mean of the polyelectrolyte multilayer tions of CD34+ and CD34- evolving in parallel. (PEM) fi lms, we develop new culture platforms for Classical endothelial (CD31) or myogenic (CD56) human muscle stem cell maintaining or expansion for markers were maintained during ageing. In DMD pa- either therapeutic purpose but also for fundamental tients, however, despite their young age, the ALDH+/ studies on muscle development in physiological and CD34- sub-population is decreased as compared to pathological conditions. The tools are developed by controls, and the proportion of CD45+ cells (hemato- micro- and nano-engineering for the study of cellular poietic cells, monocytes) is increased. Cell cultures and multi-cellular responses. The innovation of our prepared from these DMD biopsies yielded far less biomaterial relies on the combination of mechanical ALDH+/CD56+ progenitors than controls. In young (stiffness), biochemical (peptide grafting to target control and mdx Mice, the proportions of ALDH+ specifi c surface receptors, growth factor presentation) cells were comparable, but they decreased in mdx af- or topographical stimuli that can be spatially con- ter the classical acute cycle of degeneration-regenera- trolled (fi gure 1). Our work is at the fundament level tion observed around the fourth week.Taken together, to further understand muscle development in physio- these results support the hypothesis that these cell logical and pathological conditions but also in view of populations are associated with muscle homeostasis future therapeutic trials. and regeneration. Other cell types
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