The growth or production of hematopoietic stem cells (stem cells that give rise to all blood cell types) is known as proliferation, and when cells are in a resting state, not actively proliferating, it is known as quiescence. While it was believed that quiescence took place because of a lack nutrients or stimulation, meaning the cell had no other option but to rest, researchers at Baylor College of Medicine now say this process is actively regulated.
The findings appear in the current edition of PLoS ONE.
To rest or not
"Our findings show that hematopoietic stem cells make the choice to stay in quiescence. This process is regulated by the protein G0S2," said Dr. Daniel Lacorazza, assistant professor of pathology and immunology at BCM and researcher with Texas Children's Hospital. "This type of stem cell is important because there are only a limited number that produce all our blood cells. So in a way the stem cells are balancing between proliferation and quiescence so they don't get exhausted."
Researchers began with a gene expression analysis of proliferating and nonproliferating cells and noted that G0S2 was upregulated (an increase of a cellular component) in quiescence. When Lacorazza looked specifically to hematopoietic stem cells, he and his colleagues noted there were high levels of G0S2, and when proliferation began, the levels reduced.
Mechanisms for quiescence
"We forced expression of G0S2 and found that we could increase the state of quiescence, so it is a positive regulator," Lacorazza said. "Our next question was how does it regulate this process; what are the mechanisms."
Using mass spectrometry, they began to look for proteins that interacted with G0S2 and identified nucleolin, a protein that promotes cell growth and proliferation. Lacorazza said that when G0S2 binds with nucleolin it retains it in the cytosol (the liquid found inside a cell), not allowing it to enter the nucleus and performing its proper function.
"In a sense G0S2 sequesters the nucleolin outside the nucleus of the cell extending quiescence," Lacorazza said.
Implicated in many diseases
Hematopoietic stem cells and G0S2 are implicated in many diseases such as certain forms of leukemia and inflammatory disorders; however there is no direct link. Lacorazza said the findings are helping researchers move closer to understanding the functions of normal stem cells that may one day help better understand how to target leukemic stem cells in the treatment of leukemia.
Others who contributed to this study include Dr. Takeshi Yamada, instructor in pathology & immunology; Drs. Chun Shik Park and Audrea Burns, both postdoctoral associates in pathology & immunology; Dr. Daisuke Nakada, associate professor in molecular and human genetics. All are with BCM.
The authors would like to thank the staff of the Flow Cytometry laboratory at Texas Children's Hospital.
Funding for this study came from the NIH National Institute of Allergy and Infectious Diseases and the Gabrielle's Angel Foundation for Cancer Research.