Hematopoietic stem cells (HSCs), resident in the bone marrow, are at the base of a complicated tree of descendant progenitor cells that collectively produce immune cells and red blood cells. With age, the HSC population becomes damaged and dysfunctional. The number of competent stem cells diminishes, while mutational damage followed by clonal expansion causes issues such as myeloid skew in the hematopoietic populations, in which too many myeloid cells are produced at the expense of needed lymphoid cells. This all contributes to an age-related decline in immune system function. Given the importance of the immune system to health and aging, there is considerable interest in finding ways to restore a more youthful, functional state of hematopoiesis in older people.
Today's research materials discuss chronic infection as one of the contributing causes of HSC dysfunction. In the study of aging, the more interesting chronic infections are viral, meaning persistent herpesviruses such as cytomegalovirus that the immune system cannot fully clear. The presence of infection puts a stress on the immune system, as cells replicate more rapidly, and a greater number of replacement somatic cells are required to ensure continued function. Over longer periods of time, this can lead to exhaustion of these cell populations, both the somatic cells that only replicate a limited number of times, and the stem cells that use a fine balance of mechanisms to ensure their self-renewal and continued ability to create new somatic cells.
Humans are born with tens of thousands of hematopoietic stem cells (HSCs) that collectively ensure lifelong production of blood and immune cells that protect us from infections. HSCs can either duplicate to produce more stem cell progeny or differentiate to produce distinct immune cell lineages, an extremely critical decision that ensures that the body achieves the fine balance between having enough immune cells to fight invaders while still retaining enough HSCs to maintain future blood production. As we age, HSCs accumulate mutations that lead to the emergence of genetically distinct subpopulations. This common phenomenon known as clonal hematopoiesis (CH) is known to start in early fifties and is frequently associated with loss of function mutations in the DNMT3A gene. CH is associated with a significantly higher risk of blood cancers, cardiovascular disease, stroke, and all-cause mortality.
"Previously, we showed that chronic infection significantly impairs the ability of wild-type HSCs to remain in a quiescent stem cell state. Prolonged (lasting several months) exposure to a systemic bacterial infection promoted extensive differentiation of HSCs. While this produced sufficient immune cells to fight the infection, it also reduced the number of bone marrow HSCs by 90%. In contrast, HSCs in mice lacking Dnmt3a gene did not differentiate much. In fact, they underwent self-renewal to produce more HSCs. We undertook the current study to test our prediction that defective differentiation and increased duplication of Dnmt3a HSCs allows them to overtake and outcompete normal HSCs when fighting chronic infections or facing long-term inflammatory conditions."
Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras.
We created Dnmt3a-mosaic mice by transplanting Dnmt3a-/- and wild type (WT) HSCs into WT mice and observed the substantial expansion of Dnmt3a-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a-/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a-/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.