Tristetraprolin overexpression drives hematopoietic changes in young and middle-aged mice generating dominant mitigating effects on induced inflammation in murine models.

Tristetraprolin (TTP), encoded by Zfp36 in mice, is one of the best-characterized tandem zinc-finger mRNA binding proteins involved in mRNA deadenylation and decay. TTPΔARE mice lack an AU-rich motif in the 3'-untranslated regions of TTP mRNA, leading to increased TTP mRNA stability and more TTP protein, resulting in elevated mRNA decay rates of TTP targets. We examined the effect of TTP overexpression on the hematopoietic system in both young and middle-aged mice using TTPΔARE mice and found alterations in blood cell frequencies, with loss of platelets and B220 cells and gains of eosinophils and T cells. TTPΔARE mice also have skewed primitive populations in the bone marrow, with increases in myeloid-biased hematopoietic stem cells (HSCs) but decreases in granulocyte/macrophage-biased multipotent progenitors (MPP3) in both young and middle-aged mice. Changes in the primitive cells' frequencies were associated with transcriptional alterations in the TTP overexpression cells specific to age as well as cell type. Regardless of age, there was a consistent elevation of transcripts regulated by TNFα and TGFß signaling pathways in both the stem and multipotent progenitor populations. HSCs with TTP overexpression had decreased reconstitution potential in murine transplants but generated hematopoietic environments that mitigated the inflammatory response to the collagen antibody-induced arthritis (CAIA) challenge, which models rheumatoid arthritis and other autoimmune disorders. This dampening of the inflammatory response was even present when there was only a small frequency of TTP overexpressing cells present in the middle-aged mice. We provide an analysis of the early hematopoietic compartments with elevated TTP expression in both young and middle-aged mice which inhibits the reconstitution potential of the HSCs but generates a hematopoietic system that provides dominant repression of induced inflammation.

The epigenetic state of the cell of origin defines mechanisms of leukemogenesis.

Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce the leukemogenic MLL-AF9 translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impart the clinical heterogeneity of AML.

Short-term periodic restricted feeding elicits metabolome-microbiome signatures with sex dimorphic persistence in primate intervention.

Dietary restriction has shown benefits in physiological, metabolic, and molecular signatures associated with aging but is a difficult lifestyle to maintain for most individuals. In mice, a less restrictive diet that allows for cyclical periods of reduced calories mitigates aging phenotypes, yet the effects of such an intervention in a genetically heterogenous, higher-order mammal has not been examined. Here, using middle-aged rhesus macaques matched for age and sex, we show that a regimen of 4 days of low-calorie intake followed by 10 days of ad libitum feeding (4:10 diet) performed in repeating cycles over 12 weeks led to significant loss of weight and fat percentage, despite the free access to food for most of the study duration. We show the 4-day restriction period is sufficient to drive alterations to the serum metabolome characterized by substantial differences in lipid classes. These phenotypes were paralleled by changes in the gut microbiome of restricted monkeys that highlight the involvement of a microbiome-metabolome axis. This regimen shows promising phenotypes, with some sex-dimorphic responses, including residual memory of the diet. As many calorie restriction interventions are difficult to sustain, we propose that this short-term diet may be easier to adhere to and have benefits directly relevant to human aging.

Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo.

Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null (Tert-/-) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert-/- mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert-/- hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert-/- transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

Developmental maturation of the hematopoietic system controlled by a Lin28b-let-7-Cbx2 axis.

Hematopoiesis changes over life to meet the demands of maturation and aging. Here, we find that the definitive hematopoietic stem and progenitor cell (HSPC) compartment is remodeled from gestation into adulthood, a process regulated by the heterochronic Lin28b/let-7 axis. Native fetal and neonatal HSPCs distribute with a pro-lymphoid/erythroid bias with a shift toward myeloid output in adulthood. By mining transcriptomic data comparing juvenile and adult HSPCs and reconstructing coordinately activated gene regulatory networks, we uncover the Polycomb repressor complex 1 (PRC1) component Cbx2 as an effector of Lin28b/let-7's control of hematopoietic maturation. We find that juvenile Cbx2-/- hematopoietic tissues show impairment of B-lymphopoiesis, a precocious adult-like myeloid bias, and that Cbx2/PRC1 regulates developmental timing of expression of key hematopoietic transcription factors. These findings define a mechanism of regulation of HSPC output via chromatin modification as a function of age with potential impact on age-biased pediatric and adult blood disorders.

NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm-/- and old mice HSCs.

NAD+ supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD+ to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD+ precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.