Clonal hematopoiesis-related mutant ASXL1 promotes atherosclerosis in mice via dysregulated innate immunity.

Certain somatic mutations provide a fitness advantage to hematopoietic stem cells and lead to clonal expansion of mutant blood cells, known as clonal hematopoiesis (CH). Among the most common CH mutations, ASXL1 mutations pose the highest risk for cardiovascular diseases (CVDs), yet the mechanisms by which they contribute to CVDs are unclear. Here we show that hematopoietic cells harboring C-terminally truncated ASXL1 mutant (ASXL1-MT) accelerate the development of atherosclerosis in Ldlr mice.

iPSC-derived megakaryocytes and platelets accelerate wound healing and angiogenesis.

Background: Platelet-rich plasma (PRP), which is prepared by concentrating platelets in autologous blood, shows efficacy in chronic skin wounds via multiple growth factors. However, it exhibits heterogeneity across patients, leading to unstable therapeutic efficacy. Human induced pluripotent stem cell (iPSC)-derived megakaryocytes and platelets (iMPs) are capable of providing a stable supply, holding promise as materials for novel platelet concentrate-based therapies.

Inhibition of TOPORS ubiquitin ligase augments the efficacy of DNA hypomethylating agents through DNMT1 stabilization.

DNA hypomethylating agents (HMAs) are used for the treatment of myeloid malignancies, although their therapeutic effects have been unsatisfactory. Here we show that CRISPR-Cas9 screening reveals that knockout of topoisomerase 1-binding arginine/serine-rich protein (TOPORS), which encodes a ubiquitin/SUMO E3 ligase, augments the efficacy of HMAs on myeloid leukemic cells with little effect on normal hematopoiesis, suggesting that TOPORS is involved in resistance to HMAs. HMAs are incorporated into the DNA and trap DNA methyltransferase-1 (DNMT1) to form DNA-DNMT1 crosslinks, which undergo SUMOylation, followed by proteasomal degradation.

Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model.

The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs.

Epigenetics of hematopoietic stem cell aging.

Purpose Of Review: The development of new antiaging medicines is of great interest to the current elderly and aging population. Aging of the hematopoietic system is attributed to the aging of hematopoietic stem cells (HSCs), and epigenetic alterations are the key effectors driving HSC aging. Understanding the epigenetics of HSC aging holds promise of providing new insights for combating HSC aging and age-related hematological malignancies.

Context-dependent modification of PFKFB3 in hematopoietic stem cells promotes anaerobic glycolysis and ensures stress hematopoiesis.

Metabolic pathways are plastic and rapidly change in response to stress or perturbation. Current metabolic profiling techniques require lysis of many cells, complicating the tracking of metabolic changes over time after stress in rare cells such as hematopoietic stem cells (HSCs). Here, we aimed to identify the key metabolic enzymes that define differences in glycolytic metabolism between steady-state and stress conditions in murine HSCs and elucidate their regulatory mechanisms.

Acute malaria suppresses the B lymphocytic niche in the bone marrow through the alteration of CXCL12-abundant reticular cells.

Bone marrow is a dynamic organ composed of stem cells that constantly receive signals from stromal cells and other hematopoietic cells in the niches of the bone marrow to maintain hematopoiesis and generate immune cells. Perturbation of the bone marrow microenvironment by infection and inflammation affects hematopoiesis and may affect immune cell development. Little is known about the effect of malaria on the bone marrow stromal cells that govern the hematopoietic stem cell (HSC) niche.

Histone H3.3 variant plays a critical role on zygote-to-oocyst development in malaria parasites.

The Plasmodium life cycle involves differentiation into multiple morphologically distinct forms, a process regulated by developmental stage-specific gene expression. Histone proteins are involved in epigenetic regulation in eukaryotes, and the histone variant H3.3 plays a key role in the regulation of gene expression and maintenance of genomic integrity during embryonic development in mice.

Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS.

A Sox17 downstream gene Rasip1 is involved in the hematopoietic activity of intra-aortic hematopoietic clusters in the midgestation mouse embryo.

Background: During mouse embryonic development, definitive hematopoiesis is first detected around embryonic day (E) 10.5 in the aorta-gonad-mesonephros (AGM) region. Hematopoietic stem cells (HSCs) arise in the dorsal aorta's intra-aortic hematopoietic cell clusters (IAHCs).

[Identification of transcriptional features and surface markers of plasma cell clones in POEMS syndrome by single-cell RNA sequencing].

POEMS syndrome is a rare monoclonal plasma cell disorder with unique symptoms distinct from other plasma cell neoplasms. To identify and find the transcriptional features of clonal plasma cells in POEMS syndrome (POEMS clones), single-cell RNA sequencing was performed on patient-derived bone marrow plasma cells. POEMS clones were identified in 5 out of 10 patients, and the proportions of POEMS clones in the plasma cells were markedly smaller than that of other plasma cell malignancies such as multiple myeloma and MGUS.

Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis.

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.

UTX inactivation in germinal center B cells promotes the development of multiple myeloma with extramedullary disease.

UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of the X-linked Utx in germinal center (GC) derived cells collaborates with the activating Braf mutation and promotes induction of lethal GC/post-GC B cell malignancies with MM-like plasma cell neoplasms being the most frequent. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia.

Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits.

Soft tissue sarcomas (STSs) are a heterogeneous group of tumors that originate from mesenchymal cells. p53 is frequently mutated in human STS. In this study, we found that the loss of p53 in mesenchymal stem cells (MSCs) mainly causes adult undifferentiated soft tissue sarcoma (USTS).

Replication stress increases mitochondrial metabolism and mitophagy in FANCD2 deficient fetal liver hematopoietic stem cells.

Fanconi Anemia (FA) is an inherited bone marrow (BM) failure disorder commonly diagnosed during school age. However, in murine models, disrupted function of FA genes leads to a much earlier decline in fetal liver hematopoietic stem cell (FL HSC) number that is associated with increased replication stress (RS). Recent reports have shown mitochondrial metabolism and clearance are essential for long-term BM HSC function.

Chemically defined cytokine-free expansion of human haematopoietic stem cells.

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo.

Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia.

We investigated the role of Hoip, a catalytic subunit of linear ubiquitin chain assembly complex (LUBAC), in adult hematopoiesis and myeloid leukemia by using both conditional deletion of Hoip and small-molecule chemical inhibitors of Hoip. Conditional deletion of Hoip led to significantly longer survival and marked depletion of leukemia burden in murine myeloid leukemia models. Nevertheless, a competitive transplantation assay showed the reduction of donor-derived cells in the bone marrow of recipient mice was relatively mild after conditional deletion of Hoip.