Consistency and variability of murine hematopoietic stem cell aging

Hematopoietic stem cells (HSCs), located in bone marrow, sustain life time blood production by self-renewal (maintaining stem cell pool) and differentiation (production of various blood cells). With aging, HSCs undergo functional in which both intrinsic and extrinsic mechanisms are involved. The aim of the work presented in this thesis is to investigate the crosstalk between intrinsic and extrinsic factors in HSC aging. We uncovered a HSC aging signature, reflecting consistent intrinsic changes of aged HSCs at molecular level. By comparing the transcriptome of aged HSCs isolated from two genetically distinct strains of mice, B6 and DBA/2J (D2), we identified genetically conserved and non-conserved molecular changes. We then investigated the role of the most consistent differentially expressed HSC aging gene, P-selectin (Selp), in HSC aging. Finally, we showed that the transcriptome of aged HSCs is strongly affected by the aging bone marrow (BM) microenvironment. Our work highlights the notion that HSC aging is driven by both intrinsic and extrinsic factors

Inflammation and Aging of Hematopoietic Stem Cells in Their Niche

Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood cell lineages. The functioning of aged HSCs is impaired, including a declined repopulation capacity and myeloid and platelet-restricted differentiation. Both cell-intrinsic and microenvironmental extrinsic factors contribute to HSC aging. Recent studies highlight the emerging role of inflammation in contributing to HSC aging. In this review, we summarize the recent finding of age-associated changes of HSCs and the bone marrow niche in which they lodge, and discuss how inflammation may drive HSC aging

Megakaryopoiesis impairment through acute innate immune signaling activation by azacitidine

Publisher Copyright: © 2022 Okoye-Okafor et al.Thrombocytopenia, prevalent in the majority of patients with myeloid malignancies, such as myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), is an independent adverse prognostic factor. Azacitidine (AZA), a mainstay therapeutic agent for stem cell transplant–ineligible patients with MDS/AML, often transiently induces or further aggravates disease-associated thrombocytopenia by an unknown mechanism. Here, we uncover the critical role of an acute type-I interferon (IFN-I) signaling activation in suppressing megakaryopoiesis in AZA-mediated thrombocytopenia. We demonstrate that megakaryocytic lineage-primed progenitors present IFN-I receptors and, upon AZA exposure, engage STAT1/SOCS1-dependent downstream signaling prematurely attenuating thrombopoietin receptor (TPO-R) signaling and constraining megakaryocytic progenitor cell growth and differentiation following TPO-R stimulation. Our findings directly implicate RNA demethylation and IFN-I signal activation as a root cause for AZA-mediated thrombocytopenia and suggest mitigation of TPO-R inhibitory innate immune signaling as a suitable therapeutic strategy to support platelet production, particularly during the early phases of AZA therapy.Peer reviewe

A comprehensive transcriptome signature of murine hematopoietic stem cell aging

We surveyed 16 published and unpublished data sets to determine whether a consistent pattern of transcriptional deregulation in aging murine hematopoietic stem cells (HSC) exists. Despite substantial heterogeneity between individual studies, we uncovered a core and robust HSC aging signature. We detected increased transcriptional activation in aged HSCs, further confirmed by chromatin accessibility analysis. Unexpectedly, using 2 independent computational approaches, we established that deregulated aging genes consist largely of membrane-associated transcripts, including many cell surface molecules previously not associated with HSC biology. We show that Selp (P-selectin), the most consistent deregulated gene, is not merely a marker for aged HSCs but is associated with HSC functional decline. Additionally, single-cell transcriptomics analysis revealed increased heterogeneity of the aged HSC pool. We identify the presence of transcriptionally "young-like" HSCs in aged bone marrow. We share our results as an online resource and demonstrate its utility by confirming that exposure to sympathomimetics or deletion of Dnmt3a/b molecularly resembles HSC rejuvenation or aging, respectively

Calibration Strategy of the JUNO-TAO Experiment

The Taishan Antineutrino Observatory (JUNO-TAO, or TAO) is a satellite detector for the Jiangmen Underground Neutrino Observatory (JUNO). Located near the Taishan reactor, TAO independently measures the reactor's antineutrino energy spectrum with unprecedented energy resolution. To achieve this goal, energy response must be well calibrated. Using the Automated Calibration Unit (ACU) and the Cable Loop System (CLS) of TAO, multiple radioactive sources are deployed to various positions in the detector to perform a precise calibration of energy response. The non-linear energy response can be controlled within 0.6% with different energy points of these radioactive sources. It can be further improved by using $^{12}\rm B$ decay signals produced by cosmic muons. Through the energy non-uniformity calibration, residual non-uniformity is less than 0.2%. The energy resolution degradation and energy bias caused by the residual non-uniformity can be controlled within 0.05% and 0.3%, respectively. In addition, the stability of other detector parameters, such as the gain of each silicon photo-multiplier, can be monitored with a special ultraviolet LED calibration system

Calibration Strategy of the JUNO-TAO Experiment

The Taishan Antineutrino Observatory (JUNO-TAO, or TAO) is a satellite detector for the Jiangmen Underground Neutrino Observatory (JUNO). Located near the Taishan reactor, TAO independently measures the reactor's antineutrino energy spectrum with unprecedented energy resolution. To achieve this goal, energy response must be well calibrated. Using the Automated Calibration Unit (ACU) and the Cable Loop System (CLS) of TAO, multiple radioactive sources are deployed to various positions in the detector to perform a precise calibration of energy response. The non-linear energy response can be controlled within 0.6% with different energy points of these radioactive sources. It can be further improved by using $^{12}\rm B$ decay signals produced by cosmic muons. Through the energy non-uniformity calibration, residual non-uniformity is less than 0.2%. The energy resolution degradation and energy bias caused by the residual non-uniformity can be controlled within 0.05% and 0.3%, respectively. In addition, the stability of other detector parameters, such as the gain of each silicon photo-multiplier, can be monitored with a special ultraviolet LED calibration system