An NIAID research team has identified a gene called Lin28b that causes adult bone marrow cells, known as hematopoietic stem cells (HSCs), to acquire some of the attributes of fetal HSCs, which can mature into any immune cell type. Converting adult HSCs into fetal-like HSCs with Lin28b opens up the possibility of improving the treatment of certain cancers and immune diseases. The study findings appeared online in the Feb. 16, 2012, issue of Science.
Fetal HSCs can mature into the full spectrum of immune cell types needed in the body, including infection-fighting T cells and antibody-producing B cells. Adult HSCs currently are used in bone marrow transplants for people with certain cancers and immune diseases, but they have a limited ability to mature into the various immune cell types. Finding a way to convert adult HSCs into more fetal-like HSCs provides the opportunity to improve the success of transplants using adult bone marrow.
Researchers led by Stefan Muljo, Ph.D., chief of the Integrative Immunobiology Unit in the Laboratory of Immunology, observed that Lin28b is turned on in fetal HSCs and turned off in adult HSCs. Prior to this study little was understood about the factors that differentiated fetal HSCs and adult HSCs.
In mouse studies, researchers observed that turning on Lin28b expression in adult HSCs favored the development of immune cell types that normally only come from fetal HSCs, including types of T and B cells that respond rapidly to defend the host. As a result, adult mice given adult HSCs with active Lin28b develop a more complete immune system than mice given normal adult HSCs without active Lin28b. Gene analysis revealed that Lin28b expression in adult mouse HSCs turns on additional genes associated with fetal cells, while turning off some genes associated with adult cells.
The team's findings indicate that Lin28b expression is a key feature distinguishing fetal from adult HSCs in mice and humans. Lin28b may be a master regulatory gene for fetal HSC development that also is capable of reprogramming adult HSCs.
The NIAID research team currently is investigating how Lin28b reprograms adult cells. They also are working to understand what turns on Lin28b in fetal cells and what turns it off in adult cells. Through a better understanding of how and why Lin28b regulates fetal HSC development, researchers will be able to explore Lin28b in therapeutic strategies.
The ability to convert adult HSCs into fetal-like cells could be a breakthrough for people with blood or immune diseases who need a bone marrow transplant. Finding a suitable donor can take months and does not guarantee that the transplant will be successful. Graft-versus-host disease—a condition in which the donated cells attack the recipient's cells, tissues, or organs—also is a significant risk for any transplant. Using Lin28b-reprogrammed adult HSCs in a transplant offers the potential for the blood and immune system to develop anew, similar to how the immune system develops in a fetus or a newborn. Converting adult HSCs into more fetal-like cells with Lin28b also offers an easy and ethical way to further study fetal HSCs in the laboratory.
Yuan J, Nguyen CK, Liu X, Kanellopoulou C, Muljo SA. Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science. 2012 Feb 16. [Epub ahead of print].
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Last Updated April 04, 2012