TISSUE-SPECIFIC STEM CELLS
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1 TISSUE-SPECIFIC STEM CELLS Brief Report: Blockade of Notch Signaling in Muscle Stem Cells Causes Muscular Dystrophic Phenotype and Impaired Muscle Regeneration SHUIBIN LIN, a HUANGXUAN SHEN, a,b BAOFENG JIN, a,c YUMEI GU, a ZIRONG CHEN, a CHUNXIA CAO, a CHENGBIN HU, a CHARLES KELLER, d WARREN S. PEAR, e LIZI WU a a Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, Florida, USA; b State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People s Republic of China; c Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, People s Republic of China; d Pediatric Cancer Biology Program, Pape Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA; e Department of Pathology and Laboratory Medicine and Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA Key Words. Notch Muscular dystrophy Muscle stem cells Myogenesis ABSTRACT Muscular dystrophies are a group of devastating diseases characterized by progressive muscle weakness and degeneration, with etiologies including muscle gene mutations and regenerative defects of muscle stem cells. Notch signaling is critical for skeletal myogenesis and has important roles in maintaining the muscle stem cell pool and preventing premature muscle differentiation. To investigate the functional impact of Notch signaling blockade in muscle stem cells, we developed a conditional knock-in mouse model in which endogenous Notch signaling is specifically blocked in muscle stem cell compartment. Mice with Disclosure of potential conflicts of interest is found at the end of this article. Notch signaling inhibition in muscle stem cells showed several muscular dystrophic features and impaired muscle regeneration. Analyses of satellite cells and isolated primary myoblasts revealed that Notch signaling blockade in muscle stem cells caused reduced activation and proliferation of satellite cells but enhanced differentiation of myoblasts. Our data thus indicate that Notch signaling controls processes that are critical to regeneration in muscular dystrophy, suggesting that Notch inhibitor therapies could have potential side effects on muscle functions. STEM CELLS 2013;31: INTRODUCTION Skeletal muscle is capable of initiating a highly regulated myogenic process leading to muscle growth, maintenance, and repair [1, 2]. This process is mainly dependent upon a quiescent pool of stem cells (satellite cells). In response to growth, injury, or increased exercise, satellite cells become activated and proliferate as mononucleated progenitor cells (myoblasts), which then differentiate into multinucleated myotubes and further mature as functional muscles. Importantly, satellite cells are able to self-renew to replenish the stem cell pool for further rounds of muscle regeneration. Muscular dystrophies are a heterogeneous group of devastating diseases characterized by progressive muscle weakness and degeneration [3], and currently there are no effective treatments. The development and progression of muscular dystrophies is a result of multiple factors including muscle gene mutations and cell-autonomous failure in muscle stem cells [3 5]. Currently, stem cell-mediated therapeutic strategies such as muscle stem cell transplantation or functional enhancement of endogenous muscle stem cells are being pursued to improve muscle functions and pathology in muscular dystrophy patients [2, 3, 6, 7]. However, the development of effective therapies requires a better understanding of molecular and cellular mechanisms regulating muscle stem cell behaviors. Notch signaling is a developmental signaling pathway with critical roles in the highly coordinated muscle regenerative process [8 11]. Notch signaling is required for muscle stem cell maintenance as well as their proliferation and activation in response to regenerative cues [8 12]. At a later stage of myogenesis, when sufficient myoblasts are produced, Notch signaling must be switched off to allow myoblast differentiation and subsequent reconstitution of functional muscles, as Notch activation blocks myogenic differentiation Author contributions: S.L.: collection of data, data analysis and interpretation, and manuscript writing; H.S., B.J., Y.G., Z.C., C.C. and C.H.: collection of data; C.K.: provision of study materials and manuscript writing; W.S.P.: provision of study materials; L.W.: conception and design, data analysis and interpretation, and manuscript writing. Correspondence: Lizi Wu, Ph.D., Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, 2033 Mowry Road, Gainesville, Florida , USA. Telephone: ; Fax: ; lzwu@ufl.edu. Received June 7, 2012; Revised November 23, 2012; accepted for publication November 27, 2012; first published online in STEM CELLS EXPRESS January 10, VC AlphaMed Press /2013/$30.00/0 doi: /stem.1319 STEM CELLS 2013;31:
2 824 Notch Blockade Causes Muscle Defects Figure 1. Generation of mice with Notch signaling inhibition in muscle stem cells. (A): The ROSA26 dnmaml1/dnmaml1 mice were crossed with Pax7-Cre mice to generate Pax7-Cre þ /dnmaml1 þ (Mutant) and Pax7-Cre /dnmaml1 þ mice (Control). The mutant mice expressed the Notch inhibitor dnmaml1-gfp in the Pax7-positive cell compartments including muscle stem cells (satellite cells). (B, C): The mutant mice had smaller size (B) and lower body weight (C), as compared to the control littermates, and showed hair loss on the head area (B). Data were collected from 2-month-old mice. n ¼ 3. *, p <.05. (D): The mutant mice also showed spinal deformation. A 6-month-old mouse is shown. (E): The mutant mice had a shortened life span when compared to the controls. n ¼ 8. [9]. Therefore, Notch signaling is critical in maintaining an appropriate population of muscle progenitor cells and preventing premature differentiation [9]. However, specific stages of the myogenic process that require Notch signaling have not been rigorously determined, since genetic analysis mainly focused on a CSL-deficient mouse model [8, 11, 13]. CSL is the Notch pathway transcription factor with dual functions as a transcriptional repressor or activator in the absence or presence of Notch receptor activation, respectively [14]; consequently, CSL deficiency leads to de-repression of, or loss of, Notch target gene transcription depending on cellular Notch status. Differential functional impacts on myogenic differentiation were observed as CSL depletion blocked murine C2C12 myoblast differentiation, whereas inhibition of active Notch signaling via c-secretase inhibitor promoted differentiation (unpublished data). Therefore, a more rigorous genetic model is needed to investigate Notch-dependent myogenic step(s) and how Notch signaling deregulation might affect muscle functions. Understanding the knowledge gaps regarding the in vivo roles of Notch signaling in muscle stem cells is important because Notch signaling modulation is being widely investigated in the treatment of diseases and tissue regeneration [15, 16]. Here, we developed a mouse model in which a pan-notch inhibitor dnmaml1 specifically blocks Notch signaling in muscle stem cells. Our data revealed that Notch signaling blockade in muscle stem cells might affect the development and progression of muscular dystrophies. MATERIALS AND METHODS Detailed materials and methods were provided as supporting information. RESULTS AND DISCUSSION To study the functional impact of blocking endogenous active Notch signaling in muscle stem cells, we crossed ROSA26 dnmaml1/dnmaml1 mice [17] with Pax7-Cre mice [18] to generate offsprings including Pax7-Cre þ /dnmaml1 þ (Mutants) and Pax7-Cre /dnmaml1 þ littermate controls (Fig. 1A). dnmaml1 is a 62-amino-acid peptide derived from the Notch coactivator MAML1 that interferes with the ability of MAML coactivators to form Notch transcriptional complexes (Notch/CSL/MAML) [19, 20], thereby blocking transcription induced by all Notch receptors. Therefore, the mutant mice expressed the pan-notch inhibitor dnmaml1- gfp in muscle stem cells driven by the Pax7 promoter.
3 Lin, Shen, Jin et al. 825 Figure 2. The Pax7-Creþ/dnMAML1þ mutant mice exhibited muscular dystrophic phenotypes. (A, B): The mutant mice had smaller muscle masses (A) and lower weight (B). Data were collected from the gastrocnemius muscles of about 2-month-old mice. n ¼ 6. **, p <.01. (C): H&E staining of gastrocnemius muscles revealed severe muscle damage and active muscle degeneration indicated by the central nucleated myofibers (arrow). The lower panel is the enlarged picture of the square region in the upper one. (D): The Gomori s Trichrome staining revealed the presence of fibrous tissues (arrow) in the muscle samples of the mutant mice. The lower panel is the enlarged picture of the square region in the upper one. (E): The mutant muscles had a significant reduction in the number of Pax7-positive satellite cells. Data were collected from Pax7 immunohistochemical staining of gastrocnemius muscles at p15 (postnatal day 15) and p30. n ¼ 3. **, p <.01; *, p <.05. (F, G): The mutant muscles showed a significant increase in the number of MyoD-positive activated satellite cells in comparison to the control muscles. Immunohistochemical staining of MyoD (arrow) in the gastrocnemius muscles of p30 control and mutant mice were shown (F). The number of MyoD-positive cells per field was presented (G). n ¼ 3. ***, p <.001. We observed that the Pax7-Creþ/dnMAML1þ mutant mice were smaller in size and weight (Fig. 1B, 1C), displayed muscle weakness and poor balance (dragging both hind limbs simultaneously when walking) (supporting information Video S1), showed hair loss on the head (Fig. 1B, 1D), and some developed spinal deformation (Fig. 1D) and hydrocephalus (not shown) after 2 6 months of age. These mice had a shortened life span and the majority died within 8 months after birth (Fig. 1E). The mutant mice had major muscle defects with smaller muscle masses (Fig. 2A, 2B). Histological analysis of the severely abnormally moving mice revealed that the mutants had severe muscle damage and degeneration as indicated by the central nucleated myofibers (Fig. 2C) as well as fibrous tissue replacement in their muscles (Fig. 2D), suggesting that Notch-depleted satellite cells are inefficient to repair muscle damages induced by normal activity. The mutant muscles had a significantly reduced number of Pax7-positive satellite cells in both p15 and p30 mice (Fig. 2E) but enhanced number of MyoD-positive myogenic cells (Fig. 2F, 2G). These data suggest that satellite cell depletion in the mutant mice possibly results from reduced self-renewal and excessive myogenic commitment/differentiation of satellite cells [8, 11, 12]. Moreover, primary myoblasts isolated from the mutant mice showed reduced proliferative capacity (Fig. 3A) comwww.stemcells.com pared to the controls, but no change in cellular apoptosis (not shown), which is consistent with previous reports [8, 11]. The mutant myoblasts were prone to differentiation as shown by the generation of larger and longer myofibers (Fig. 3B) and increased expression of muscle differentiation markers Myogenin and Myosin (Fig. 3C). Thus, Notch loss-of-function causes premature differentiation and reduced proliferation of muscle stem cells, suggesting that deregulated Notch signaling contributes to the dystrophic phenotype. We next determined the effect of Notch signaling inhibition in satellite cells on muscle regenerative capacity in vivo in response to cardiotoxin-induced injury. Muscle regeneration consists of two key steps: the initial activation and proliferation of muscle stem cells, and subsequent myogenic differentiation to restore the functional muscles. At day 1 after injury, Pax7 expression was lower in the mutant mice (Fig. 4A 4C), suggesting that Notch signaling inhibition results in reduced satellite cell activation and proliferation. The defects in stem cells likely affected the later myogenic differentiation, as reduced induction of myogenic transcription factor Myogenin was observed 3 days postinjury (Fig. 4D). At day 7, control muscles reconstituted with numerous newly regenerated centrally nucleated myofibers (Fig. 4E), whereas mutant muscles consisted of the majority of smaller regenerated myofibers,
4 826 Notch Blockade Causes Muscle Defects Figure 3. Myoblasts from the Pax7-Cre þ /dnmaml1 þ mutant mice showed reduced proliferation but enhanced differentiation. (A): Primary myoblasts were isolated and cultured in growth medium. Cell proliferation was determined by cell counting at indicated days. (B, C): The mutant myoblasts were prone to differentiation. The myoblasts were induced to differentiate by switching from growth medium to differentiation medium (2% horse serum in Dulbecco s modified Eagle s medium). Myosin staining (green) was performed 3 days later using an anti-myosin antibody and the nuclei were counter-stained with DAPI (4,6-diamidino-2-phenylindole) (B). Cell lysates were collected at various time points for Western blot analysis of the expression of early differentiation marker Myogenin and late differentiation marker Myosin (C). with some showing abnormally large but hollow (Fig. 4F) or absence of the nuclei (Fig. 4G). Therefore, Notch inhibition in muscle stem cells results in defective regenerative capacity, which is consistent with a role of Notch signaling in maintaining and activation of muscle stem cells [8, 11]. It should be noted that a prenatal patterning and other defects cannot be excluded because of Pax7-cre expression in fetal muscles as well as other tissues [18]. Future work using mouse models with Notch inhibition postnatally will provide conclusive evidence for a role of active Notch signaling in muscle regeneration. Most importantly, we showed that Notch signaling inhibition likely affect the pathogenesis or progression of muscular dystrophy diseases. Therefore, potential side effects of Notch inhibitors on muscle functions for the treatment of cancers and other diseases should be considered, although short-tem Notch inhibition appeared not to affect muscles in a clinically symptomatic way [21]. of Notch signaling in muscle stem cell maintenance and differentiation. The Pax7-Cre þ /dnmaml1 þ mutant mice exhibit several important muscular dystrophic features and impaired muscle regeneration. Therefore, impaired Notch signaling likely contributes to the pathogenic mechanisms of muscular dystrophies. Long-term clinical applications of Notch inhibitors might have significant side effects on muscle functions. ACKNOWLEDGMENTS We thank Dr. Moyi Li for the technical help with muscle injection, Marda Jorgensen for helping with immunohistochemical staining, and Dr. Abigail McElhinny for critical reading of this manuscript and helpful comments. This work is supported in part by the University of Florida Shands Cancer Center Startup fund (L.W) and Muscular Dystrophy Association (L.W). CONCLUSION We used a specific genetic tool, the pan-notch inhibitor dnmaml1, to block endogenous active Notch signaling in muscle stem cell compartment and revealed a critical role DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST The authors indicate no potential conflicts of interest.
5 Lin, Shen, Jin et al. 827 Figure 4. The in vivo muscle regenerative capacities of the mutant mice were impaired. (A C): Tibialis anterior (TA) muscles were injected with cardiotoxin to induce muscle injury and regeneration. At day 1 postinjection, muscle samples were collected for immunohistochemical staining (A and B) and real-time polymerase chain reaction (PCR) analysis (C) of Pax7 expression. n ¼ 3. *, p <.05; ***, p <.001. (D): At 3 days after injection, RNA samples were collected from the control and mutant TA muscles, and real-time RT-PCR was performed to determine the relative transcript levels of Myogenin (n ¼ 3. **, p <.01). (E G): H&E staining was performed on the TA muscles from control (E) and mutant (F, G) mice at 7 days after cardiotoxin injection, and the lower panels are enlarged pictures of the square region in the upper ones. REFERENCES 1 Le Grand F, Rudnicki M. Satellite and stem cells in muscle growth and repair. Development 2007;134: Shi X, Garry DJ. Muscle stem cells in development, regeneration, and disease. Genes Dev 2006;20: Wallace GQ, McNally EM. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Annu Rev Physiol 2009;71: Sacco A, Mourkioti F, Tran R et al. Short telomeres and stem cell exhaustion model Duchenne muscular dystrophy in mdx/mtr mice. Cell 2010;143: Gnocchi VF, Ellis JA, Zammit PS. Does satellite cell dysfunction contribute to disease progression in Emery-Dreifuss muscular dystrophy? Biochem Soc Trans 2008;36: Quattrocelli M, Cassano M, Crippa S et al. Cell therapy strategies and improvements for muscular dystrophy. Cell Death Differ 2010;17: Bentzinger CF, von Maltzahn J, Rudnicki MA. Extrinsic regulation of satellite cell specification. Stem Cell Res Ther 2010;1:27.
6 828 Notch Blockade Causes Muscle Defects 8 Bjornson CR, Cheung TH, Liu L et al. Notch signaling is necessary to maintain quiescence in adult muscle stem cells. Stem Cells 2012;30: Buas MF, Kadesch T. Regulation of skeletal myogenesis by Notch. Exp Cell Res 2010;316: Conboy IM, Conboy MJ, Smythe GM et al. Notch-mediated restoration of regenerative potential to aged muscle. Science 2003;302: Mourikis P, Sambasivan R, Castel D et al. A critical requirement for notch signaling in maintenance of the quiescent skeletal muscle stem cell state. Stem Cells 2012;30: Wen Y, Bi P, Liu W et al. Constitutive Notch activation upregulates Pax7 and promotes the self-renewal of skeletal muscle satellite cells. Mol Cell Biol 2012;32: Vasyutina E, Lenhard DC, Wende H et al. RBP-J (Rbpsuh) is essential to maintain muscle progenitor cells and to generate satellite cells. Proc Natl Acad Sci USA 2007;104: Borggrefe T, Oswald F. The Notch signaling pathway: Transcriptional regulation at Notch target genes. Cell Mol Life Sci 2009;66: Fouillade C, Monet-Lepretre M, Baron-Menguy C et al. Notch signalling in smooth muscle cells during development and disease. Cardiovasc Res 2012;95: Groth C, Fortini ME. Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Semin Cell Dev Biol 2012;23: Tu L, Fang TC, Artis D et al. Notch signaling is an important regulator of type 2 immunity. J Exp Med 2005;202: Keller C, Hansen MS, Coffin CM et al. Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: Implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev 2004;18: Wu L, Aster JC, Blacklow SC et al. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000;26: McElhinny AS, Li JL, Wu L. Mastermind-like transcriptional co-activators: Emerging roles in regulating cross talk among multiple signaling pathways. Oncogene 2008;27: Fouladi M, Stewart CF, Olson J et al. Phase I trial of MK-0752 in children with refractory CNS malignancies: A pediatric brain tumor consortium study. J Clin Oncol 2011;29: See for supporting information available online.
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