"There are many clinical challenges facing our patients that could be met if we could expand stem cell populations," says David Scadden, MD, director of the MGH CRMT, the paper's senior author. "The ability to enhance the number of stem cells an individual produces could have an immediate impact on patient care."
Clinical use of hematopoietic stem cells has always been difficult because they naturally occur in very small numbers and rarely reproduce. In recent years, many research groups have sought ways to expand stem cell populations, often by adding growth factors to bone marrow samples. The MGH researchers took a different approach by focusing on the natural environment in which stem cells develop, which in adults is the marrow cavity inside long bones.
Stem cells are usually found in the outer layer of marrow, adjacent to the inner layer of bone. This observation suggested that osteoblasts – cells that generate new bone tissue to replace old bone and are found in that inner bone region – might also have an impact on stem cells. To investigate that possibility, the researchers first studied a group of transgenic mice with an overly active version of a protein that turns on osteoblasts. They found that, in addition to having excessive numbers of osteoblasts in their bones, the mice also had increased levels of stem cells in their bone marrow, although the amount of other marrow cells was normal. Further testing confirmed that this activated protein, a receptor for the bone-building parathyroid hormone (PTH), could be acting through a cellular-signalling pathway called Notch that is known to increase stem cell proliferation.
Following those findings, the researchers investigated whether injections of PTH – an FDA-approved treatment for osteoporosis developed through MGH research – might produce the same stem cell effect as seen in the transgenic mice. They first injected a group of normal mice with the hormone, and found similarly increased levels of stem cells in the bone marrow after 4 weeks' treatment. They then conducted bone marrow transplants on mice that had been irradiated to destroy their marrow, and found that marrow from mice treated with PTH was more effective in replacing recipient marrow than was tissue from normal mice.
To simulate the sort of situation facing many patients needing stem cell transplants, the research team carried out a bone marrow transplant protocol including marrow destruction and the transfer of only a few stem cells on mice that had previously received PTH injections and on a control group. Where only 27 percent of the control mice survived for 28 days after transplantation, all of the PTH-treated mice survived, and examination of their marrow confirmed that the donor tissue had proliferated.
"Treatment with PTH had a remarkable effect on these animals' recovery from bone marrow transplantation," says Scadden, an associate professor of Medicine at Harvard Medical School. "This work opens a new angle from which we can attack the challenges of stem cell transplantation, focusing on the environment to achieve a stem cell effect."
Scadden and his colleagues will soon be initiating clinical trials to analyze the effect of PTH treatment of both stem cell donors and recipients. They also will investigate whether the hormone can help expand stem cells populations outside the body, such as the tiny amounts that are found in banked samples of umbilical cord blood.
The co-first authors of the Nature study are Laura Calvi, MD, formerly of the MGH Endocrinology Unit and now at the University of Rochester Medical School; and Gregor Adams, PhD, of CRMT, Partners AIDS Research Center (PARC) and the MGH Cancer Center. Other co-authors include Katherine Weibrecht, Douglas Olson, and Roderick Martin, of CRMT/PARC/MGH Cancer Center; Melissa Knight, Ernestina Schipani, MD, PhD, Paola Divieti, Richard Bringhurst, MD, and Henry Kronenberg, MD, of the MGH Endocrine Unit; and Jon Weber and Laurie Milner, MD, of Rochester. The study was supported by grants from the National Institutes of Health, the American Society of Hematology, the Doris Duke Foundation and the Burroughs Wellcome Fund.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
Journal
Nature