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Miller, Christine

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Miller

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Christine

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Miller, Christine
Author's Publications: search.filters.isAuthorOfPublication.c49c46f4-1e33-4812-b038-02170472d727

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    Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
    (Elsevier BV, 2013) Loffredo, F; Steinhauser, Matthew; Jay, Steven M.; Gannon, Joseph; Pancoast, James R.; Yalamanchi, Pratyusha; Sinha, Manisha; Dall’Osso, Claudia; Khong, Danika; Shadrach, Jennifer; Miller, Christine; Singer, Britta S.; Stewart, Alex; Psychogios, Nikolaos; Gerszten, Robert; Hartigan, Adam J.; Kim, Mi-Jeong; Serwold, Thomas; Wagers, Amy; Lee, Richard
    The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-b superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
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    Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle
    (American Association for the Advancement of Science (AAAS), 2014) Sinha, Manisha; Jang, Y. C.; Oh, Juhyun; Khong, Danika; Wu, Elizabeth Y; Manohar, Rohan; Miller, Christine; Regalado, Samuel G.; Loffredo, F; Pancoast, James R.; Hirshman, Michael; Lebowitz, Jessica; Shadrach, Jennifer; Cerletti, Massimiliano; Kim, Mi Jeong; Serwold, Thomas; Goodyear, Laurie; Rosner, Bernard; Lee, Richard; Wagers, Amy
    Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.
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    Diminished Schwann Cell Repair Responses Underlie Age-Associated Impaired Axonal Regeneration
    (Elsevier BV, 2014) Painter, Michio; Brosius Lutz, Amanda; Cheng, Yung-Chih; Latremoliere, Alban; Duong, Kelly; Miller, Christine; Posada, Sean; Cobos, Enrique J.; Zhang, Alan; Wagers, Amy; Havton, Leif A.; Barres, Ben; Omura, Takao; Woolf, Clifford
    The regenerative capacity of the peripheral nervous system declines with age. Why this occurs, however, is unknown. We demonstrate that 24-month-old mice exhibit an impairment of functional recovery after nerve injury compared to 2-month-old animals. We find no difference in the intrinsic growth capacity between aged and young sensory neurons in vitro or in their ability to activate growth-associated transcriptional programs after injury. Instead, using age-mismatched nerve transplants in vivo, we show that the extent of functional recovery depends on the age of the nerve graft, and not the age of the host. Molecular interrogation of the sciatic nerve reveals that aged Schwann cells (SCs) fail to rapidly activate a transcriptional repair program after injury. Functionally, aged SCs exhibit impaired dedifferentiation, myelin clearance, and macrophage recruitment. These results suggest that the age-associated decline in axonal regeneration results from diminished Schwann cell plasticity, leading to slower myelin clearance.
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    Induction of Histiocytic Sarcoma in Mouse Skeletal Muscle
    (Public Library of Science, 2012) Liu, Jianing; Hettmer, Simone; Milsom, Michael D.; Hofmann, Inga; Hua, Frederic; Miller, Christine; Bronson, Roderick; Wagers, Amy
    Myeloid sarcomas are extramedullary accumulations of immature myeloid cells that may present with or without evidence of pathologic involvement of the bone marrow or peripheral blood, and often coincide with or precede a diagnosis of acute myeloid leukemia (AML). A dearth of experimental models has hampered the study of myeloid sarcomas and led us to establish a new system in which tumor induction can be evaluated in an easily accessible non-hematopoietic tissue compartment. Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19−/− bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice. In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30–50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers. Tumor cells also infiltrated the bone marrow, spleen and other non-hematopoietic organs of tumor-bearing animals, leading to systemic illness (leukemia) within two weeks of tumor detection. P16/p19−/−; Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation. The systemic leukemic phenotypes exhibited by histiocytic sarcoma-bearing mice were nearly identical to those of animals in which leukemia was introduced by intravenous transplantation of the same donor cells. Moreover, murine histiocytic sarcoma could be similarly induced by intramuscular injection of MLL-AF9 leukemia cells. This study establishes a novel, transplantable model of murine histiocytic/myeloid sarcoma that recapitulates the natural progression of these malignancies to systemic disease and indicates a cell autonomous leukemogenic mechanism.