July 29, 2005

Bone marrow may be source of new egg-cell generation in adult mammals

Last year a group of MGH researchers announced finding that female mice — contrary to longstanding theories — retained the ability to make new oocytes (egg cells) into adulthood. Now the same investigators have identified a potential source for the production of these cells — stem cells in the bone marrow. Their article appears in the July 29 issue of Cell. "We may be ushering in a new era in the clinical management of female infertility and menopause," says Jonathan Tilly, PhD, director of the Vincent Center for Reproductive Biology at the MGH and leader of the research team (right). "This could lead to new treatment approaches based not on drugs but on regenerative medicine through adult stem cells."

Last year's report contradicted the biological "dogma" that female mammals are born with a limited supply of oocytes that are depleted throughout life. Instead, the MGH team found evidence that adult female mice are constantly producing new oocytes and follicles, the tiny sacs in which eggs grow. In the current paper, they first showed that, while injections of the chemotherapy drug doxorubicin kill existing oocytes and follicles, hundreds of follicles reappear within 24 hours, suggesting there is another source of oocytes not damaged by the drug.

A search for gene markers known to be associated with the germ cells that produce oocytes in embryonic animals found that "every germ cell marker we could think of was expressed in the bone marrow of adult female mice," Tilly says. To verify the presence of germline stem cells in bone marrow, the researchers ran a series of experiments in female mice that had been sterilized with powerful chemotherapy doses and in mice that lacked a gene essential for the development of mature oocytes. In both groups, mice who received bone marrow from normally fertile females soon began to produce normal-appearing oocytes. In a series of similar experiments involving blood cell transfusions, the previously sterile mice began to produce oocytes within two days.

Tilly explains that it now looks like the ovary is part of a three-tiered system in which stem cells in the bone marrow manufacture progenitor germ cells, which travel through the bloodstream to the ovary, where they mature into oocyte-containing follicles. "This shows that we need to think more broadly about female reproduction — that oocyte production involves more than just the ovaries," he says. Future studies will examine whether the oocytes produced after blood or marrow transplants can produce offspring and search for the molecular signal that induces the bone marrow to produce progenitor cells.

The paper's co-authors are first author Joshua Johnson, PhD, Malgorzata Skaznik-Wikiel, MD, Ho-Joon Lee, PhD, Yuichi Niikura, PhD, Katherine Tschudy, PhD, and Jacqueline Canning Tilly, all from the Vincent Center for Reproductive Biology, along with Jessamyn Bagley, PhD, Gregor Adams, PhD, Maria Cortes, PhD, Randolf Forkert, PhD, Thomas Spitzer, MD, John Iacomini, PhD, and David Scadden, MD.