Perspectives

Hematopoietic stem cells gone rogue

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Science  24 Feb 2017:
Vol. 355, Issue 6327, pp. 798-799
DOI: 10.1126/science.aam7939

Cardiovascular disease is considered to be an aging-related disease and is the leading cause of death in the elderly in developed countries (1). As of 2013, 65% of deaths attributed to cardiovascular disease occurred among patients 75 years and older. A hallmark of aging is the accumulation of somatic DNA mutations in proliferative tissue. Although somatic mutations in the hematopoietic (blood cell) system are frequently observed in patients with hematological cancers, there is also a close correlation between hematopoietic somatic mutations and increased incidence of diabetes, atherosclerosis, and cardiovascular disease-related deaths (2). On page 842 of this issue, Fuster et al. (3) report that somatic mutation in a gene called ten-eleven translocation 2 (Tet2) in hematopoietic stem cells increases atherosclerosis development in a mouse model.

TET2 encodes an epigenetic regulatory enzyme that mediates DNA demethylation by catalyzing the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine. It also exerts noncatalytic actions including controlling mast cell proliferation (46). TET2 catalytic activity is critical for maintaining normal development of hematopoietic stem progenitor cells (HSPCs) (7). Mutations in TET2 are among the most frequently occurring mutations in blood cells (2). Loss of Tet2 in smooth muscle cells correlates with increased intimal vascular injury in mice (8). TET2 expression is also reduced in human atherosclerotic arteries (8). This suggests a potential relationship between TET2 mutations in hematopoietic cells, clonal hematopoiesis, and atherosclerosis.

Fuster et al. developed an elegant experimental mouse model to observe hematopoietic stem cell differentiation and proliferation. The authors transplanted bone marrow into mice that were genetically engineered to be susceptible to atherosclerosis [the animals lacked the gene encoding low density lipoprotein receptor (Ldlr)]. Only 10% of the transplanted bone marrow cells lacked Tet2, yet they produced three times more mature leukocytes than did normal bone marrow cells. By feeding these mice a high cholesterol diet, the authors determined how the loss of Tet2 function, and therefore the aberrant hematopoietic stem cell expansion, affects atherosclerosis. They observed that if given Tet2-deficient bone marrow cells, mice developed 60% larger aortic plaques compared to control mice that received normal bone marrow. They also observed that approximately 60% of the immune cellular composition in the atherosclerotic vascular wall was derived from bone marrow cells lacking Tet2. Interestingly, over 60% of these cells preferentially differentiated into macrophages. Thus, hematopoietic Tet2 deficiency caused an enormous expansion of the macrophage pool. To confirm the role of Tet2-deficient macrophages in inducing atherosclerosis, Fuster et al. generated a mouse model in which Tet2 was deficient specifically in myeloid cells, including macrophages. These mice indeed developed more atherosclerosis than wild-type control animals. Importantly, the authors discovered that Tet2-deficient macrophages showed a substantial increase in the production of the proinflammatory cytokine interleukin 1β (IL-1β).


Embedded Image

Lack of Tet2 causes a large expansion of the macrophage pool from hematopoietic stem cells (colored scanning electron micrograph of fetal blood stem cells shown).

PHOTO: STEVE GSCHMEISSNER/SCIENCE SOURCE

Tet2 regulation of IL-1β secretion could account for the proatherogenic features of macrophages. Fuster et al. found that Tet2 influences IL-1β production in multiple ways that are independent of its catalytic abilities (see the figure). When the repressive effect of Tet2 was blocked indirectly [by blocking histone deacetylase (HDAC)], IL-1β production in wild-type macrophages was increased to levels similar to that of Tet2-deficient macrophages. Tet2 deficiency increased both the production of the precursor form of IL-1β (pro-IL-1β) and the activity of the inflammasome complex [called NLR family pyrin domain containing 3 (NLRP3)] activity, which increases the conversion of pro-IL-1β to active IL-1β. Interestingly, treatment of macrophages lacking Tet2 with an NLRP3 inhibitor abrogated IL-1β production. The inhibitor also eliminated differences in aortic plaque formation between the mice that received either wild-type bone marrow or bone marrow lacking Tet2. Thus, Fuster et al. demonstrate that loss of Tet2 aggravates atherosclerosis by promoting HSPC differentiation into macrophages, and by increasing macrophage inflammation, through a mechanism that is independent of Tet2 catalytic activity.

Although Fuster et al. clearly point to Tet2 control of macrophage function as important, the potential roles of loss of Tet2 in other immune cells derived from donor bone marrow cells in the mouse model system were not examined. The authors observed an increase in T cells, B cells, and neutrophils in their model, but they did not examine the role of Tet2 deficiency in these cell types on atherosclerosis progression. The boost in IL-1β production increased the expression of P-selectin in the aortic arch, but whether this affected monocyte recruitment into the aortic wall and their differentiation into proatherogenic macrophages was not determined. Fuster et al. also found that atherosclerosis was reduced when animals were treated with an NLRP3 inhibitor, indicating that the effect was independent of Tet2-deficient cellular expansion. This suggests that in atherosclerosis, the main role for Tet2 loss in HSPCs is increasing the production of IL-1β by macrophages rather than increasing the hyperproliferative potential of macrophages. It would be interesting to dissect the role of Tet2 loss in proliferation alone, without its effect on IL-1β, on the incidence of atherosclerosis.

The idea that the noncatalytic activities of TET2 promote atherosclerosis opens the door for investigating the role of TET2 in other somatic mutation-related diseases such as cancer. Emerging evidence suggests that TET2 mutations that occur in HSPCs are not solely responsible for the prognosis of hematological malignancies, but rather, provide a clonal advantage that leads to a myeloid differentiation bias and expansion of the stem cell pool. Investigation of TET2 noncatalytic activities in these diseases may greatly expand our knowledge of disease outcome from somatic mutations.

Targeting Tet2

Loss of functional Tet2 in macrophages increases IL-1β gene expression, NLRP3 activity, and the production and release of inflammatory IL-1β. This promotes atherosclerosis. HDAC, histone deacetylase; Ac, acetyl group.

GRAPHIC: A. KITTERMAN/SCIENCE

DNA methylation and histone acetylation have been identified as potential drug targets for treating cardiovascular disease. Inhibition of DNA methylation by 5-aza-2′-deoxycytidine, a DNA methyltransferase inhibitor, prevents atherosclerosis lesion formation and reduces the production of inflammatory cytokines by macrophages (911). The findings of Fuster et al. indicate that designing strategies to target loss-of-function mutations in TET2 could potentially be a therapeutic intervention for dampening cardiovascular disease. Antibodies that neutralize IL-1 show promising results in clinical trials for patients with acute myocardial infarction (12). If combined with a treatment that targets TET2 mutations, cardiovascular disease and other agingrelated diseases may be dealt a powerful blow indeed (13, 14).

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