Jamie Brett

All Publications

• Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo CELL REPORTS van Velthoven, C. J., de Morree, A., Egner, I. M., Brett, J. O., Rando, T. A. 2017; 21 (7): 1994–2004

  Abstract

  Muscle stem cells (MuSCs) persist in a quiescent state and activate in response to specific stimuli. The quiescent state is both actively maintained and dynamically regulated. However, analyses of quiescence have come primarily from cells removed from their niche. Although these cells are still quiescent, biochemical changes certainly occur during the isolation process. Here, we analyze the transcriptome of MuSCs in vivo utilizing MuSC-specific labeling of RNA. Notably, labeling transcripts during the isolation procedure revealed very active transcription of specific subsets of genes. However, using the transcription inhibitor α-amanitin, we show that the ex vivo transcriptome remains largely reflective of the in vivo transcriptome. Together, these data provide perspective on the molecular regulation of the quiescent state at the transcriptional level, demonstrate the utility of these tools for probing transcriptional dynamics in vivo, and provide an invaluable resource for understanding stem cell state transitions.

  View details for DOI 10.1016/j.celrep.2017.10.037

  View details for Web of Science ID 000415073200023

  View details for PubMedID 29141228

  View details for PubMedCentralID PMC5711481

• An artificial niche preserves the quiescence of muscle stem cells and enhances their therapeutic efficacy. Nature biotechnology Quarta, M., Brett, J. O., DiMarco, R., de Morree, A., Boutet, S. C., Chacon, R., Gibbons, M. C., Garcia, V. A., Su, J., Shrager, J. B., Heilshorn, S., Rando, T. A. 2016; 34 (7): 752-759

  Abstract

  A promising therapeutic strategy for diverse genetic disorders involves transplantation of autologous stem cells that have been genetically corrected ex vivo. A major challenge in such approaches is a loss of stem cell potency during culture. Here we describe an artificial niche for maintaining muscle stem cells (MuSCs) in vitro in a potent, quiescent state. Using a machine learning method, we identified a molecular signature of quiescence and used it to screen for factors that could maintain mouse MuSC quiescence, thus defining a quiescence medium (QM). We also engineered muscle fibers that mimic the native myofiber of the MuSC niche. Mouse MuSCs maintained in QM on engineered fibers showed enhanced potential for engraftment, tissue regeneration and self-renewal after transplantation in mice. An artificial niche adapted to human cells similarly extended the quiescence of human MuSCs in vitro and enhanced their potency in vivo. Our approach for maintaining quiescence may be applicable to stem cells isolated from other tissues.

  View details for DOI 10.1038/nbt.3576

  View details for PubMedID 27240197

  View details for PubMedCentralID PMC4942359

• mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert). Nature Rodgers, J. T., King, K. Y., Brett, J. O., Cromie, M. J., Charville, G. W., Maguire, K. K., Brunson, C., Mastey, N., Liu, L., Tsai, C., Goodell, M. A., Rando, T. A. 2014; 510 (7505): 393-396

  Abstract

  A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.

  View details for DOI 10.1038/nature13255

  View details for PubMedID 24870234

  View details for PubMedCentralID PMC4065227

• Alive and well? Exploring disease by studying lifespan CURRENT OPINION IN GENETICS & DEVELOPMENT Brett, J. O., Rando, T. A. 2014; 26: 33-40

  Abstract

  A common concept in aging research is that chronological age is the most important risk factor for the development of diverse diseases, including degenerative diseases and cancers. The mechanistic link between the aging process and disease pathogenesis, however, is still enigmatic. Nevertheless, measurement of lifespan, as a surrogate for biological aging, remains among the most frequently used assays in aging research. In this review, we examine the connection between 'normal aging' and age-related disease from the point of view that they form a continuum of aging phenotypes. This notion of common mechanisms gives rise to the converse postulate that diseases may be risk factors for accelerated aging. We explore the advantages and caveats associated with using lifespan as a metric to understand cell and tissue aging, focusing on the elucidation of molecular mechanisms and potential therapies for age-related diseases.

  View details for DOI 10.1016/j.gde.2014.05.004

  View details for Web of Science ID 000345060800006

  View details for PubMedCentralID PMC4253307

• Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nature cell biology Rafalski, V. A., Ho, P. P., Brett, J. O., Ucar, D., Dugas, J. C., Pollina, E. A., Chow, L. M., Ibrahim, A., Baker, S. J., Barres, B. A., Steinman, L., Brunet, A. 2013; 15 (6): 614-624

  Abstract

  Oligodendrocytes-the myelin-forming cells of the central nervous system-can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK-signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.

  View details for DOI 10.1038/ncb2735

  View details for PubMedID 23644469

  View details for PubMedCentralID PMC4026158

• The MicroRNA Cluster miR-106b similar to 25 Regulates Adult Neural Stem/Progenitor Cell Proliferation and Neuronal Differentiation AGING-US Brett, J. O., Renault, V. M., Rafalski, V. A., Webb, A. E., Brunet, A. 2011; 3 (2): 108-124

  Abstract

  In adult mammals, neural stem cells (NSCs) generate new neurons that are important for specific types of learning and memory. Controlling adult NSC number and function is fundamental for preserving the stem cell pool and ensuring proper levels of neurogenesis throughout life. Here we study the importance of the microRNA gene cluster miR-106b~25 (miR-106b, miR-93, and miR-25) in primary cultures of neural stem/progenitor cells (NSPCs) isolated from adult mice. We find that knocking down miR-25 decreases NSPC proliferation, whereas ectopically expressing miR-25 promotes NSPC proliferation. Expressing the entire miR-106b~25 cluster in NSPCs also increases their ability to generate new neurons. Interestingly, miR-25 has a number of potential target mRNAs involved in insulin/insulin-like growth factor-1 (IGF) signaling, a pathway implicated in aging. Furthermore, the regulatory region of miR-106b~25 is bound by FoxO3, a member of the FoxO family of transcription factors that maintains adult stem cells and extends lifespan downstream of insulin/IGF signaling. These results suggest that miR-106b~25 regulates NSPC function and is part of a network involving the insulin/IGF-FoxO pathway, which may have important implications for the homeostasis of the NSC pool during aging.

  View details for Web of Science ID 000288170400008

  View details for PubMedID 21386132

  View details for PubMedCentralID PMC3082007

• FoxO3 Regulates Neural Stem Cell Homeostasis CELL STEM CELL Renault, V. M., Rafalski, V. A., Morgan, A. A., Salih, D. A., Brett, J. O., Webb, A. E., Villeda, S. A., Thekkat, P. U., Guillerey, C., Denko, N. C., Palmer, T. D., Bufte, A. J., Brunet, A. 2009; 5 (5): 527-539

  Abstract

  In the nervous system, neural stem cells (NSCs) are necessary for the generation of new neurons and for cognitive function. Here we show that FoxO3, a member of a transcription factor family known to extend lifespan in invertebrates, regulates the NSC pool. We find that adult FoxO3(-/-) mice have fewer NSCs in vivo than wild-type counterparts. NSCs isolated from adult FoxO3(-/-) mice have decreased self-renewal and an impaired ability to generate different neural lineages. Identification of the FoxO3-dependent gene expression profile in NSCs suggests that FoxO3 regulates the NSC pool by inducing a program of genes that preserves quiescence, prevents premature differentiation, and controls oxygen metabolism. The ability of FoxO3 to prevent the premature depletion of NSCs might have important implications for counteracting brain aging in long-lived species.

  View details for DOI 10.1016/j.stem.2009.09.014

  View details for Web of Science ID 000272019500014

  View details for PubMedID 19896443

  View details for PubMedCentralID PMC2775802