Hematopoietic stem cells (HSC) in aging mice preferentially lose the ability to regenerate the adaptive immune system. This skewing towards production of myeloid cells and other HSC abnormalities may contribute to the immunosenescence seen in humans. That is, the quality of responses to vaccination can be poor or inappropriate in aged individuals. The circumstances that elicit these changes and the underlying mechanisms are largely unknown. While HSC are harmed by chemotherapy, radiation, DNA repair defects, loss of telomerase and elevated cytokines, selective loss of lymphopoietic potential has not been reported in those circumstances. In contrast, we have found myeloid skewing, defective self-renewal and other age-related changes in HSC recovered from mice repeatedly exposed to very low doses of lipopolysaccharide. This is despite the fact that the animals were in generally good health and numbers of HSC were normal. These remarkable findings suggest that persistent low-grade infections and associated pathogen products might cause HSC senescence and ultimately compromise immunity. It is possible that similar HSC changes are caused by endogenous Toll- like receptor (TLR) ligands associated with tissue damage and obesity. We will now determine if the phenomenon occurs with other TLR ligands and in an animal model of inflammatory bowel disease (IBD). Additionally, we will explore the means through which HSC are harmed. The findings are expected to be informative about normal aging as well as many chronic conditions such as HIV/AIDS that may accelerate immunosenescence. Also, a basis may be found for age-related shifts in patterns of some hematopoietic malignancies.

Public Health Relevance

Our immune systems become less effective in old age, and there is new evidence to suggest this can result from a history of low-grade infections. More study could reveal how to block or even reverse these consequences of aging.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107138-03
Application #
8269672
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2010-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$403,425
Indirect Cost
$155,925
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Iida, Ryuji; Welner, Robert S; Zhao, Wanke et al. (2014) Stem and progenitor cell subsets are affected by JAK2 signaling and can be monitored by flow cytometry. PLoS One 9:e93643
Welner, Robert S; Kincade, Paul W (2014) 9-1-1: HSCs respond to emergency calls. Cell Stem Cell 14:415-6
Satoh, Yusuke; Yokota, Takafumi; Sudo, Takao et al. (2013) The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages. Immunity 38:1105-15
Zhang, Qingzhao; Iida, Ryuji; Yokota, Takafumi et al. (2013) Early events in lymphopoiesis: an update. Curr Opin Hematol 20:265-72
Shimazu, Tomoyuki; Iida, Ryuji; Zhang, Qingzhao et al. (2012) CD86 is expressed on murine hematopoietic stem cells and denotes lymphopoietic potential. Blood 119:4889-97
Zhang, Qingzhao; Iida, Ryuji; Shimazu, Tomoyuki et al. (2012) Replenishing B lymphocytes in health and disease. Curr Opin Immunol 24:196-203
Esplin, Brandt L; Shimazu, Tomoyuki; Welner, Robert S et al. (2011) Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol 186:5367-75
Ichii, Michiko; Oritani, Kenji; Yokota, Takafumi et al. (2010) The density of CD10 corresponds to commitment and progression in the human B lymphoid lineage. PLoS One 5:e12954