Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review

“…Recently, Sano et al confirmed the casual relationship between Tet2-mutated clone expansion and the development of HF in non-irradiated mice that have not been preconditioned by a myeloablative strategy [49]. In this study, mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac hypertrophy and fibrosis that were associated with an increased inflammatory signature in donor-derived Tet2-deficient interstitial macrophages [49]. This observation could be explained by the fact that, in murine macrophages and dendritic cells, Tet2 represses the transcription of pro-inflammatory molecules such as IL-6, a known pro-atherogenic mediator (even if this IL-6-driven atherogenic effect has been reported to be independent, at least in part, of the well-known enzymatic role of TET2 [39,40]).…”

“…The same group, in 2018 [48], found that deletion of either Tet2 or Dnmt3A in bone marrow caused increased cardiac hypertrophy and fibrosis and a reduction in cardiac function in mice with angiotensin-II-induced HF, suggesting that the reduced survival rate seen in patients with TET2 or DNMT3A mutations is causally related to altered immune cell function in the myocardium [39,40]. Recently, Sano et al confirmed the casual relationship between Tet2-mutated clone expansion and the development of HF in non-irradiated mice that have not been preconditioned by a myeloablative strategy [49]. In this study, mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac hypertrophy and fibrosis that were associated with an increased inflammatory signature in donor-derived Tet2-deficient interstitial macrophages [49].…”

The role of clonal haematopoiesis in cardiovascular diseases: epidemiology and experimental studies

“…In avoiding myeloablative strategies, clonal haematopoiesis experiments can also be conducted under conditions that more faithfully mimic the regulatory mechanisms associated with native haematopoiesis [50,51]. In view of these issues, Wang et al [52] developed a new model of murine clonal haematopoiesis that employs the adoptive transfer of unfractionated bone marrow cells to mice that have not been preconditioned by a myeloablative strategy. In these experiments, the delivery of wild-type bone marrow cells led to a low but stable engraftment of donor-derived long-term haematopoietic stem cells (LT-HSC) and various HSPC fractions, and minimally contributed to circulating leucocyte populations and resident immune cell populations in the heart and other tissues.…”

“…It has recently been reported that clonal haematopoiesis is associated with accelerated biological ageing based upon measurements of the 'epigenetic clock' that assesses the methylation patterns at specific CpG sites [53]. Although preliminary, the work of Wang et al [52] provides evidence of a potential causal link between clonal haematopoiesis and the pace of biological ageing.…”

Genome-wide association studies identify 137 loci for DNA methylation biomarkers of ageing

“…IEAA and Hannum age acceleration share the following associations: TERT, TRIM59, KPNA4, RP11-432B6.3, IFT80, and TET2. TET2 is particularly interesting in light of its mechanistic role (catalysing the conversion of methylcytosine to 5-hydroxymethylcytosine) and its established role in several ageing/regenerative phenotypes[51,52]. Several of the GWAS overlapping genes in the European ancestry analysis (e.g.…”