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Brack, Andrew S

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Brack

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Andrew S

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Brack, Andrew S
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    Pax7 is back
    (BioMed Central, 2014) Brack, Andrew S
    Two recent studies have reinvigorated the conversation regarding the role of Pax7 in adult satellite. Studies by Gunther et al (Cell Stem Cell 13:590–601, 2013) and Von Maltzhen et al (Proc Natl Acad Sci U S A 110:16474–16479) show that Pax7 is critical for adult satellite cell function and their contribution to muscle repair. Previously, Lepper et al (Nature 460:627–631, 2009) demonstrated that Pax7 was dispensable for adult muscle repair. In this commentary I have summarized the results from these studies, focusing on the differences in experimental paradigms that led the authors to different conclusions. I also take this opportunity to discuss the potential limitations and hurdles of Cre-lox technology that are responsible for the discrepant results.
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    Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA
    (Elsevier BV, 2010) Warren, Luigi; Manos, Philip D.; Ahfeldt, Tim; Loh, Yuin-Han; Li, Hualin; Lau, Frank; Ebina, Wataru; Mandal, Pankaj; Smith, Zachary; Meissner, Alexander; Daley, George; Brack, Andrew S; Collins, James; Cowan, Chad; Schlaeger, Thorsten; Rossi, Derrick
    Clinical application of induced pluripotent stem cells (iPSCs) is limited by the low efficiency of iPSC derivation and the fact that most protocols modify the genome to effect cellular reprogramming. Moreover, safe and effective means of directing the fate of patient-specific iPSCs toward clinically useful cell types are lacking. Here we describe a simple, nonintegrating strategy for reprogramming cell fate based on administration of synthetic mRNA modified to overcome innate antiviral responses. We show that this approach can reprogram multiple human cell types to pluripotency with efficiencies that greatly surpass established protocols. We further show that the same technology can be used to efficiently direct the differentiation of RNA-induced pluripotent stem cells (RiPSCs) into terminally differentiated myogenic cells. This technology represents a safe, efficient strategy for somatic cell reprogramming and directing cell fate that has broad applicability for basic research, disease modeling, and regenerative medicine.
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    Lineage of origin in rhabdomyosarcoma informs pharmacological response
    (Cold Spring Harbor Laboratory Press, 2014) Abraham, Jacob; Nunez-Alvarez, Y.; Hettmer, Simone; Carrio, E.; Chen, Hung-I Harry; Nishijo, K.; Huang, Elaine; Prajapati, Suresh I.; Walker, Robert L.; Davis, Sean; Rebeles, Jennifer; Wiebush, Hunter; McCleish, Amanda T.; Hampton, Sheila T.; Bjornson, Christopher R.R.; Brack, Andrew S; Wagers, Amy; Rando, Thomas A.; Capecchi, Mario R.; Marini, Frank C.; Ehler, Benjamin R.; Zarzabal, Lee Ann; Goros, Martin W.; Michalek, Joel E.; Meltzer, Paul S.; Langenau, David; LeGallo, Robin D.; Mansoor, Asif Imran; Chen, Yidong; Suelves, Monica; Rubin, Brian P.; Keller, Charles
    Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.
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    The aged niche disrupts muscle stem cell quiescence
    (2012) Chakkalakal, Joe V.; Jones, Kieran M.; Basson, M. Albert; Brack, Andrew S
    SUMMARY The niche is a conserved regulator of stem cell quiescence and function. During aging, stem cell function declines. To what extent and by which means age-related changes within the niche contribute to this phenomenon are unknown. We demonstrate that the aged muscle stem cell niche, the muscle fiber, expresses FGF2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose self-renewing capacity. We show that relatively dormant aged satellite cells robustly express Sprouty1 (spry1), an inhibitor of FGF signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing spry1, results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of FGFR1 signalling or overexpression of spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function.