Jonathan L. Tilly, Ph.D.

       
   
      












   Brief Overview of Tilly Lab Research

Director, Vincent Center for Reproductive Biology, Massachusetts 
    General Hospital 
Chief, Division of Research, Vincent Obstetrics and Gynecology Service, 
     Massachusetts General Hospital 
Professor, Department of Obstetrics, Gynecology and 
    Reproductive Biology, Harvard Medical School
Affiliated Faculty, Harvard Stem Cell Institute

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The long-term goal of work in my laboratory is to improve women’s reproductive healthcare and overcome infertility by applying what we discover through basic and translational (preclinical) research. For over 15 years, a primary focus of my research group has been to understand the roles and regulation of the physiological cell death program termed apoptosis in the mammalian ovary (Nature Rev Mol Cell Biol 2001 2: 838-848). The majority of our work uses mouse models, which possess the advantage of relatively straightforward genetic manipulation. Since we started this work in the early 1990s, we have documented that premature ovarian failure and infertility resulting from conventional anti-cancer treatments involves the activation of apoptosis in oocytes (Nature Med 1997 3: 1228-1232; Genes Dev 1998 12: 1304-1314; Mol Endocrinol 1999 13: 841-850). We then validated an anti-apoptotic small molecule that protects the ovaries from side-effect damage caused by conventional caner treatments as a means to preserve normal reproductive function (Nature Med 1997 3:1228-1232; Nature Med 2000 6: 1109-1114; Nature Med 2002 8: 901-902), and we have recently taken this small molecule and its mimetics into preclinical testing using rhesus monkeys as a model.

In related work, we have demonstrated that polycyclic aromatic hydrocarbons (PAHs), which are toxic chemicals present at high abundance in the environment and in cigarette smoke, activate an orphan receptor-transcription factor (termed the aryl hydrocarbon receptor or AhR) in oocytes, leading to de novo expression of pro-apoptotic genes necessary for oocyte death (e.g., Bax) and early ovarian failure. Specifically, we reported that the AhR is abundantly expressed in oocytes, and that Ahr gene knockout in female mice leads to increased oocyte survival (Endocrinology 2000 141: 450-453). Moreover, in subsequent studies (Nature Genet 2001 28: 355-360; Endocrinology 2002 143: 615-620), we showed that the chemically-activated AhR induces Bax gene transcription in oocytes, and that expression of both the Ahr and Bax genes are functionally required for these chemicals to cause oocyte depletion and ovarian failure. Using a human ovarian xenograft model, we have further shown that an induction of Bax gene expression and apoptosis occurs in human primordial and primary oocytes following PAH exposure in vivo (Nature Genet 2001 28: 355-360). These data have been expanded on in a comprehensive study that details the global changes in expression of a large cassette of pro-apoptotic genes (in addition to Bax) in the ovaries following PAH exposure, and the requirement for p53 in working with the AhR to initiate oocyte apoptosis and follicle loss.

In addition to this work on pathological models of ovarian failure, we have shown that targeted inactivation of the pro-apoptotic Bax gene in mice prolongs ovarian lifespan into very advanced age, thereby eliminating the “mouse equivalent” of menopause (Nature Genet 1999 21: 200-203). This animal model has allowed us to explore, for the first time, the impact of sustained ovarian function on the aging female body, and to decipher the contribution of age-related ovarian failure versus the aging process itself to the manifestation of various health complications often observed in women after the menopause (Proc Natl Acad Sci USA 2007 104: 5229-5234).

Recently, the primary focus of our research changed from cell death to cell renewal, based on our studies that challenge one of the most basic doctrines in our field by demonstrating the existence of putative germline stem cells that support oocyte and follicle production in the ovaries of adult female mammals. For example, we recently provided evidence that juvenile and adult female mice retain proliferative germline cells that, based on rates of oocyte degeneration and clearance, are needed to continuously replenish the oocyte-containing follicle pool (Nature 2004 428: 145-150). This project is now aimed at fully characterizing female germline stem cell function, identifying the existence of such cells in humans, and developing new strategies based on stem cell transplantation technologies for enhancing fertility and perhaps delaying age-related ovarian failure.

Progress towards completion of these objectives is exemplified by a subsequent publication from our group documenting the presence of early germ cells in bone marrow and peripheral blood of adult female mice that are capable of generating immature oocytes in the ovaries of chemotherapy-sterilized or genetically-infertile adult female recipients following transplantation (Cell 2005 122: 303-315). Further, we have shown in a very recent paper that bone marrow transplantation rescues long-term fertility in adult female mice exposed to sterilizing doses of chemotherapy (J Clin Oncol 2007 25: 3198-3204). Moreover, infusions of young adult female bone marrow into aging female mice postpones the age-related onset of infertility and markedly improves the postnatal survival rates of offspring conceived by infused aged females (AGING 2009 1: 49-57). These studies, coupled with our efforts to identify specific genes and pathways that regulate the activity of germline stem cells in adult mammalian females (Cell Cycle 2007 6: 2678-2684), are providing the foundation for our ongoing development of a high throughput screening assay for identifying novel “oogenic” factors as potential therapeutics. Although this work remains controversial in some scientific circles, independent corroboration of these concepts from other laboratories is now available (reviewed in Biol Reprod 2009 80: 2-12).