When infections occur in the body, stem cells in the blood often jump into action by multiplying and differentiating¹ into mature immune cells that can fight off illness. But repeated infections and inflammation can deplete²（耗尽） these cell populations, potentially leading to the development of serious blood conditions such as cancer. Now, a team of researchers led by biologists at the California Institute of Technology (Caltech) has found that, in mouse models, the molecule³ microRNA-146a (miR-146a) acts as a critical regulator and protector of blood-forming stem cells (called hematopoietic造血的 stem cells, or HSCs) during chronic⁴ inflammation, suggesting that a deficiency of miR-146a may be one important cause of blood cancers and bone marrow⁵ failure. The team came to this conclusion by developing a mouse model that lacks miR-146a. RNA is a polymer structured like DNA⁶, the chemical that makes up our genes⁷. MicroRNAs, as the name implies, are a class of very short RNAs that can interfere⁸ with or regulate the activities of particular genes. When subjected to a state of chronic inflammation, mice lacking miR-146a showed a decline in the overall number and quality of their HSCs; normal mice producing the molecule, in contrast, were better able to maintain their levels of HSCs despite long-term inflammation. The researchers' findings are outlined in the May 21 issue of the new journal eLIFE.

 

"This mouse with genetic⁹ deletion of miR-146a is a wonderful model with which to understand chronic-inflammation-driven tumor¹⁰ formation and hematopoietic stem cell biology during chronic inflammation," says Jimmy Zhao, the lead author of the study and a MD/PhD student in the Caltech laboratory of David Baltimore, the Robert Andrews Millikan Professor of Biology. "It was surprising that a single microRNA plays such a crucial role. Deleting it produced a profound and dramatic pathology, which clearly highlights the critical and indispensable function of miR-146a in guarding the quality and longevity¹¹ of HSCs."

 

The study findings provide, for the first time, a detailed¹² molecular¹³ connection between chronic inflammation, and bone marrow failure and diseases of the blood. These findings could lead to the discovery and development of anti-inflammatory molecules¹⁴ that could be used as therapeutics for blood diseases. In fact, the researchers believe that miR-146a itself may ultimately become a very effective anti-inflammatory molecule, once RNA molecules or mimetics can be delivered more efficiently¹⁵ to the cells of interest.

 

The new mouse model, Zhao says, also mimics¹⁶ important aspects of human myelodysplastic syndrome¹⁷ (MDS) -- a form of pre-leukemia that often causes severe anemia¹⁸, can require frequent blood transfusions¹⁹, and usually leads to acute myeloid leukemia. Further study of the model could lead to a better understanding of the condition and therefore potential new treatments for MDS.

 

"This study speaks to the importance of keeping chronic inflammation in check and provides a good rationale for broad use of safer and more effective anti-inflammatory molecules," says Baltimore, who is a coauthor of the study. "If we can understand what cell types and proteins are critically important in chronic-inflammation-driven tumor formation and stem cell exhaustion²⁰, we can potentially design better and safer drugs to intervene."

 

Funding for the research outlined in the eLIFE paper, titled "MicroRNA-146a acts as a guardian²¹ of the quality and longevity of hematopoietic stem cells in mice," was provided by the National Institute of Allergy²² and Infectious Disease; the National Heart, Lung, and Blood Institute; and the National Cancer Institute. Yvette Garcia-Flores, the lead technician in Baltimore's lab, also contributed to the study along with Dinesh Rao from UCLA and Ryan O'Connell from the University of Utah. eLIFE, a new open-access, high-impact journal, is backed by three of the world's leading funding agencies, the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust.

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