Kansas City, MO - While megakaryocytes are best known for producing platelets that heal wounds, these "mega" cells found in bone marrow also play a critical role in regulating stem cells according to new research from the Stowers Institute for Medical Research. In fact, hematopoietic stem cells differentiate to generate megakaryocytes in bone marrow. The Stowers study is the first to show that hematopoietic stem cells (the parent cells) can be directly controlled by their own progeny (megakaryocytes).

The findings from the lab Stowers Investigator Linheng Li, Ph.D., described in the Oct. 19 issue of the journal Nature Medicine, could cause researchers to rethink what they know about the workings of megakaryocytes and potentially lead to new treatments for patients recovering from chemotherapy or organ transplantation.

"Our results suggest that megakaryocytes might be used clinically to facilitate adult stem cell regeneration and to expand cultured cells for adult stem cell transplants," says Meng Zhao, Ph.D., a postdoctoral fellow at Stowers and lead author on the study.

Stowers researchers discovered that megakaryocytes directly regulate the function of murine hematopoietic stem cells--adult stem cells that form blood and immune cells and that constantly renew the body's blood supply. These cells can also develop into all types of blood cells, including white blood cells, red blood cells, and platelets.

Because of their remarkable ability to renew themselves and differentiate into other cells, hematopoietic stems cells are the focus of intense research and have been used to treat many diseases and conditions. The transplantation of isolated human hematopoietic stem cells is used in the treatment of anemia, immune deficiencies and other diseases, including cancer.

Basic research has centered on identifying and characterizing hematopoietic stem cells, however, it is still not clear how hematopoietic stem cells actually work, and how they are regulated because of the complexity of the bone marrow microenvironment. Zhao and his colleagues discovered that as a terminally differentiated progeny, megakaryocytes regulate hematopoietic stem cells by performing two previously unknown functions.

"Megakaryocytes can directly regulate the amount of hematopoietic stem cells by telling the cells when they need to keep in the quiescent stage, and when they need to start proliferating to meet increased demand," Maintaining that delicate balance is important, he adds. "You don't want to have too many or too few hematopoietic stem cells."

These findings are supported by similar research from the laboratory of Paul S. Frenette, Ph.D., at the Albert Einstein College of Medicine, also reported in the Oct. 19 issue of Nature Medicine.

Employing the advanced technology of the Institute's Cytometry, Imaging and Histology centers, the researchers examined the relationship between megakaryocytes and hematopoietic stem cells in mouse bone marrow. In the course of their research, they found that the protein transforming growth factor B1 (TGF-B1), contained in megakaryocytes, signaled quiescence of hematopoietic stem cells. They also found that when under stress from chemotherapy, megakaryocytes signaled fibroblast growth factor 1 (FGF1), to stimulate the proliferation of hematopoietic stem cells.

"Our findings suggest that megakaryocytes are required for the recovery of hematopoietic stem cells post chemotherapy," explains Li. The discovery could provide insight for using megakaryocyte-derived factors, such as TGF-B1 and FGF1, clinically to facilitate regeneration of hematopoietic stem cells, he adds.

Engineering a megakaryocyte niche (a special environment in which stem cells live and renew) that supports the growth of hematopoietic stem cells in culture, is the next step for the researchers. Zhao and his colleagues are also investigating whether a megakaryocyte niche can be used to help expand human hematopoietic stem cells in vitro and stem cell transplantation for patients.

###

Other contributors to the study include John M. Perry, Ph.D., Heather Marshall, Ph.D., Pengxu Qian, Ph.D., and Xi C. He, Ph.D., with the Stowers Institute; Aparna Venkatraman, Ph.D., with the Stowers Institute and the Centre for Stem Cell Research at Christian Medical College in Vellore, India; and Jasimuddin Ahamed, Ph.D., with the Laboratory of Blood and Vascular Biology at Rockefeller University in New York.

The Stowers Institute for Medical Research funded the research.

Lay Summary of Findings

Patients recovering from chemotherapy or organ transplantation often have dangerously low levels of blood cells--leaving them weak and vulnerable to infection. Research findings from the Stowers Institute, reported in the Oct. 19 issue of the journal Nature Medicine, describe new insights that could potentially lead to treatments for patients with low blood cell counts.

Stowers Investigator Linheng Li, Ph.D., who led the study explains that megakaryocytes, "mega" cells found in bone marrow, regulate the function of human blood stem cells--adult stem cells that form blood and immune cells and constantly renew the body's blood supply. He and his colleagues found that megakaryocytes tell blood stem cells when their services aren't needed and when they need to start proliferating to meet increased demand. Study results suggest that megakaryocytes might be used clinically to jump-start adult stem cell regeneration and to expand cultured cells for adult stem cell transplants.

About the Stowers Institute for Medical Research

The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Since then, the Institute has spent over 900 million dollars in pursuit of its mission.

Currently, the Institute is home to nearly 550 researchers and support personnel; over 20 independent research programs; and more than a dozen technology-development and core facilities.