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Analysis of lung alveolar type 2 (AT2) progenitor stem cells has highlighted fundamental mechanisms that direct their differentiation into alveolar type 1 cells (AT1s) in lung repair and disease. However, microRNA (miRNA) mediated post-transcriptional mechanisms which govern this nexus remain understudied. We show here that the let-7 miRNA family serves a homeostatic role in governance of AT2 quiescence, specifically by preventing the uncontrolled accumulation of AT2 transitional cells and by promoting AT1 differentiation. Using mice and organoid models, we demonstrate genetic ablation of let-7a1/let-7f1/let-7d cluster ( let-7afd ) in AT2 cells prevents AT1 differentiation and results in accumulation of AT2 transitional cells in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing from AT2 cells uncovered the induction of direct targets of let-7 in an oncogene feed-forward regulatory network including BACH1/EZH2/MYC which drives an aberrant fibrotic cascade. Additional analyses using CUT&RUN-sequencing revealed an epigenetic role of let-7 in induction of chromatin histone acetylation and methylation and maladaptive AT2 cell reprogramming. This study identifies let-7 as a key gatekeeper of post-transcriptional and epigenetic chromatin signals to prevent AT2-driven pulmonary fibrosis., Competing Interests: COMPETING INTERESTS F.R. is currently an employee at Vertex Pharmaceuticals. The remaining authors declare no competing interests.

Abstract: Human trafficking is a proliferating abuse within the United States in which persons who are victimized frequently interface with clinical environments across the care continuum with a variety of presentations for health needs. However, in the absence of uniform standards for evidence-based training among the health professions, recognition and response in these scenarios remains low. This case study presents a young adolescent female accessing primary care with a chief complaint of commercial sexual exploitation. The Core Competencies for Human Trafficking Response in Health Systems is used as a guiding lens for practical applications in clinical practice in provision of pediatric primary care. Health care providers in a direct service role should be prepared to respond with evidence-based, trauma-informed, culturally responsive procedures and protocols used within their scope of practice., Competing Interests: Competing interests: The authors report no conflicts of interest., (Copyright © 2025 American Association of Nurse Practitioners.)

The proinflammatory cytokine interferon gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell-surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, because it is induced upon IFN stimulation and required for IFN-dependent HSC activation. To identify the mechanism by which BST2 promotes IFN-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knockout (KO) of BST2 in a murine model does not disrupt immune cell responses to IFN-inducing mycobacterial infection. Furthermore, intravital imaging studies indicate that BST2 KO does not disrupt localization of HSCs relative to endothelial or osteoblastic niches in the bone marrow. However, using imaging-based flow cytometry, we found that IFNγ treatment shifts the lipid raft polarity of wild-type (WT) but not Bst2 -/- hematopoietic stem and progenitor cells (HSPCs). Furthermore, RNAseq analysis, reverse-phase protein array and western blot analysis of HSPCs indicate that BST2 promotes ERK1/2 phosphorylation during IFNγ-mediated stress. Overall, we find that BST2 facilitates HSC division by promoting cell polarization and ERK activation, thus elucidating a key mechanism of IFN-dependent HSPC activation. These findings inform future approaches in the treatment of cancer and bone marrow failure., Competing Interests: Conflicts of Interest Disclosure The authors declare no competing interests., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Prolonged antibiotic exposure causes dangerous hematologic side effects, including neutropenia, in up to 34% of patients. Murine studies established a link between the intestinal microbiota and hematopoiesis. To identify factors that predispose to neutropenia in pediatric patients, we evaluated changes in microbiota-derived metabolites and intestinal microbiota composition after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics or at neutropenia onset (prospective arm). Some patients were enrolled in a retrospective arm in which a stool sample was collected at the time of neutropenia during antibiotic therapy and 2-4 weeks after completion of antibiotics with recovery of blood counts. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and the type of infection or antibiotic used; however, patients with neutropenia were admitted to the intensive care unit more often and received longer courses of antibiotics. Reduced intestinal microbiome richness and, specifically, decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism, and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study shows a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Here, we investigate the contribution of long-term hematopoietic stem cells (HSCs LT ) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

It remains unknown whether and how intestinal stem cells (ISCs) adapt to inflammatory exposure and whether the adaptation leaves scars that will affect their subsequent regeneration. We investigated the consequences of inflammation on Lgr5 + ISCs in well-defined clinically relevant models of acute gastrointestinal graft-versus-host disease (GI GVHD). Utilizing single-cell transcriptomics, as well as organoid, metabolic, epigenomic, and in vivo models, we found that Lgr5 + ISCs undergo metabolic changes that lead to the accumulation of succinate, which reprograms their epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures and also in vivo following serial transplantation. Furthermore, ISCs demonstrated a reduced capacity for in vivo regeneration despite resolution of the initial inflammatory exposure, demonstrating the persistence of the maladaptive impact induced by the inflammatory encounter. Thus, inflammation imprints the epigenome of ISCs in a manner that persists and affects their sensitivity to adapt to future stress or challenges., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Haematopoietic stem cells maintain blood production throughout life. While extensively characterised using the laboratory mouse, little is known about how the population is sustained and evolves with age. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1845 single cell-derived colonies, and used phylogenetic analysis to infer the ontogeny and population dynamics of the stem cell pool. Mouse stem cells and progenitors accrue ~45 somatic mutations per year, a rate only about 2-fold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns reveal that stem and multipotent progenitor cell pools are both established during embryogenesis, after which they independently self-renew in parallel over life. The stem cell pool grows steadily over the mouse lifespan to approximately 70,000 cells, self-renewing about every six weeks. Aged mice did not display the profound loss of stem cell clonal diversity characteristic of human haematopoietic ageing. However, targeted sequencing revealed small, expanded clones in the context of murine ageing, which were larger and more numerous following haematological perturbations and exhibited a selection landscape similar to humans. Our data illustrate both conserved features of population dynamics of blood and distinct patterns of age-associated somatic evolution in the short-lived mouse.

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus., Competing Interests: Declaration of interests R.R.J. has served as a consultant or advisory board member for Postbiotics Plus, Merck, Microbiome DX, Karius, MaaT Pharma, LISCure, Seres, Kaleido, and Prolacta and has received patent license fee or stock options from Seres, Kaleido, and Postbiotics Plus. E.J.S. has served as a consultant or advisory board member for Adaptimmune, Axio, Navan, Fibroblasts, and FibroBiologics, NY Blood Center, and Celaid Therapeutics and has received patent license fee from Takeda and Affimed. J.U.P. reports research funding, intellectual property fees, and travel reimbursement from Seres Therapeutics, and consulting fees from DaVolterra, CSL Behring, Crestone Inc, and from MaaT Pharma. J.U.P. serves on an advisory board of and holds equity in Postbiotics Plus Research. J.U.P. has filed intellectual property applications related to the microbiome (reference numbers #62/843,849, #62/977,908, and #15/756,845). Memorial Sloan Kettering Cancer Center (MSK) has financial interests relative to Seres Therapeutics. E.H., M.A.J., J.L.K., and R.R.J. are inventors on a patent application by The University of Texas MD Anderson Cancer Center supported by results of the current study entitled, “Methods and Compositions for Treating Cancer therapy-induced Neutropenic Fever and/or GVHD.”, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human trafficking is a severe form of child abuse and maltreatment. Cases are pervasive and no demographic, socioeconomic status, community, or school is immune. The most effective response to human trafficking in school settings requires increased awareness and establishing policies, protocols, and procedures that support collaborative response to suspected human trafficking. School nurses are well equipped to lead these efforts. While the National Association of School Nurses acknowledges the importance of the role of the school nurse in child trafficking response in their Human Trafficking Position Statement, resources to aid school nurses in coordinated recognition and response efforts remain limited. This article reviews clinical guidance on human trafficking through a school-based lens, highlights indicators that should alert school nurses to the risk of trafficking, outlines best practices for response to abuse and exploitation, and provides additional tools and resources available to aid school nurses in their approach to caring for children experiencing trafficking.

Quiescence and differentiation of hematopoietic stem and progenitor cells (HSPC) can be modified by systemic inflammatory cues. Such cues can not only yield short-term changes in HSPCs such as in supporting emergency granulopoiesis but can also promote lasting influences on the HSPC compartment. First, inflammation can be a driver for clonal expansion, promoting clonal hematopoiesis for certain mutant clones, reducing overall clonal diversity, and reshaping the composition of the HSPC pool with significant health consequences. Second, inflammation can generate lasting cell-autonomous changes in HSPCs themselves, leading to changes in the epigenetic state, metabolism, and function of downstream innate immune cells. This concept, termed "trained immunity," suggests that inflammatory stimuli can alter subsequent immune responses leading to improved innate immunity or, conversely, autoimmunity. Both of these concepts have major implications in human health. Here we reviewed current literature about the lasting effects of inflammation on the HSPC compartment and opportunities for future advancement in this fast-developing field., Competing Interests: Conflict of Interest Disclosure The authors declare no conflicts of interest., (Copyright © 2024 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Hematologic side effects are associated with prolonged antibiotic exposure in up to 34% of patients. Neutropenia, reported in 10-15% of patients, increases the risk of sepsis and death. Murine studies have established a link between the intestinal microbiota and normal hematopoiesis. We sought to identify predisposing factors, presence of microbiota-derived metabolites, and changes in intestinal microbiota composition in otherwise healthy pediatric patients who developed neutropenia after prolonged courses of antibiotics. In this multi-center study, patients with infections requiring anticipated antibiotic treatment of two or more weeks were enrolled. Stool samples were obtained at the start and completion of antibiotics and at the time of neutropenia. We identified 10 patients who developed neutropenia on antibiotics and 29 controls matched for age, sex, race, and ethnicity. Clinical data demonstrated no association between neutropenia and type of infection or type of antibiotic used; however intensive care unit admission and length of therapy were associated with neutropenia. Reduced intestinal microbiome richness and decreased abundance of Lachnospiraceae family members correlated with neutropenia. Untargeted stool metabolomic profiling revealed several metabolites that were depleted exclusively in patients with neutropenia, including members of the urea cycle pathway, pyrimidine metabolism and fatty acid metabolism that are known to be produced by Lachnospiraceae . Our study confirms a relationship between intestinal microbiota disruption and abnormal hematopoiesis and identifies taxa and metabolites likely to contribute to microbiota-sustained hematopoiesis. As the microbiome is a key determinant of stem cell transplant and immunotherapy outcomes, these findings are likely to be of broad significance., Key Points: Neutropenia occurred in 17% of patients receiving prolonged antibiotic therapy.We found no association between neutropenia and type of infection or class of antibiotic used. Development of neutropenia after prolonged antibiotic treatment was associated with decreased prevalence of Lachnospiraceae and Lachnospiraceae metabolites such as citrulline.

Abstract: Over the past 10 years, there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady-state blood production, affecting both hematopoietic stem and progenitor cells as well as differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis. Furthermore, the state of the microbiome is now recognized to affect outcomes from hematopoietic stem cell transplant, immunotherapy, and cellular therapies for hematologic malignancies. Here we review the mechanisms by which microbiotas influence hematopoiesis in development and adulthood as well as the avenues by which microbiotas are thought to impact stem cell transplant engraftment, graft-versus-host disease, and efficacy of cell and immunotherapies. We highlight areas of future research that may lead to reduced adverse effects of antibiotic use and improved outcomes for patients with hematologic conditions., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Chronic inflammation, although subtle, puts the body in a constant state of alertness and is associated with many diseases, including cancer and cardiovascular diseases. It leads hematopoietic cells to produce and release proinflammatory cytokines, which trigger specific signaling pathways in hematopoietic stem cells (HSCs) that cause changes in proliferation, differentiation, and migration. This response is essential when HSCs are needed to produce specific blood cells to eliminate an intruder, such as a pathogenic virus, but mutant HSCs can use these proinflammatory signals to their advantage and accelerate the development of hematologic disease or malignancy. Understanding this complex process is vital for monitoring and controlling disease progression in patients. In the 2023 International Society for Experimental Hematology winter webinar, Dr. Eric Pietras (University of Colorado Anschutz Medical Campus, United States) and Dr. Katherine Y. King (Baylor College of Medicine, United States) gave a presentation on this topic, which is summarized in this review article., Competing Interests: Conflict of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. All rights reserved.)

'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Recent studies suggest that infection reprograms hematopoietic stem and progenitor cells (HSPCs) to enhance innate immune responses upon secondary infectious challenge, a process called "trained immunity." However, the specificity and cell types responsible for this response remain poorly defined. We established a model of trained immunity in mice in response to Mycobacterium avium infection. scRNA-seq analysis revealed that HSPCs activate interferon gamma-response genes heterogeneously upon primary challenge, while rare cell populations expand. Macrophages derived from trained HSPCs demonstrated enhanced bacterial killing and metabolism, and a single dose of recombinant interferon gamma exposure was sufficient to induce similar training. Mice transplanted with influenza - trained HSPCs displayed enhanced immunity against M. avium challenge and vice versa, demonstrating cross protection against antigenically distinct pathogens. Together, these results indicate that heterogeneous responses to infection by HSPCs can lead to long-term production of bone marrow derived macrophages with enhanced function and confer cross-protection against alternative pathogens., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Tumors protect themselves from immune clearance by promoting extramedullary hematopoiesis. A new study in PLOS Biology provides insights into the mechanisms underlying this process, which may hold the key to disrupting generation of the immunosuppressive tumor microenvironment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Willis, King. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chimeric antigen receptor (CAR) T cell (CAR-T) therapy represents a revolutionary treatment for patients with relapsed/refractory hematologic malignancies. However, its use can result in significant toxicities, including cytokine release syndrome (CRS), a potentially life-threatening clinical syndrome resulting from the release of proinflammatory cytokines upon T cell activation. In addition, patients who develop CRS often experience prolonged cytopenias, and those with the most severe CRS also have the longest delays in full marrow recovery. Although an association between CRS and delayed bone marrow recovery has been established, the precise mechanism underlying this phenomenon remains unknown. This study was conducted to test our hypothesis that delayed bone marrow recovery following CAR-T therapy is caused by elevation of proinflammatory cytokines, leading to apoptosis and depletion of hematopoietic stem and progenitor cells (HSPCs). SCID-beige mice bearing intraperitoneal CD19 + Raji cell tumors were treated with injection of human CD19.28z CAR T cells. Bone marrow was then harvested for analysis by flow cytometry, and HSPCs were isolated for whole-transcriptome analysis by RNA sequencing. Complete blood counts and serum cytokine levels were measured as well. A second model was developed in which SCID-beige mice were treated with murine IFN-γ (mIFN-γ), murine IL-6 (mIL-6), or both. Bone marrow was harvested, and flow cytometry assays were conducted to evaluate the degree of apoptosis and proliferation on specific HSPC populations. SCID-beige mice bearing intraperitoneal Raji cell tumors that were treated with CAR-T therapy developed CRS, with elevations of several proinflammatory cytokines, including profound elevation of human IFN-γ. Gene set enrichment analysis of RNA sequencing data revealed that genes associated with apoptosis were significantly upregulated in HSPCs from mice that developed CRS. Endothelial protein C receptor (EPCR)-negative HSCs, a subset of HSCs that is poised for terminal differentiation, was found to be specifically decreased in mice that were treated with CAR T cells. Furthermore, HSPCs were found to have increased levels of apoptosis upon treatment with mIFN-γ and mIL-6, whereas short-term HSCs and multipotent progenitors exhibited increases in proliferation with mIFN-γ treatment alone. The results from this study provide evidence that the elevation of proinflammatory cytokines following CAR-T therapy impacts the bone marrow through a combined mechanism: pluripotent HSCs that are exposed to elevated levels of IFN-γ and IL-6 undergo increased cell death, while more committed progenitor cells become more proliferative in response to elevated IFN-γ. These combined effects lead to depleted stores of repopulating HSCs and ultimately cytopenias. © 2023 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Basic leucine zipper ATF-like transcription factor 2 (BATF2), an interferon-activated immune response regulator, is a key factor responsible for myeloid differentiation and depletion of HSC during chronic infection. To delineate the mechanism of BATF2 function in HSCs, we assessed Batf2 KO mice during chronic infection and found that they produced less pro-inflammatory cytokines, less immune cell recruitment to the spleen, and impaired myeloid differentiation with better preservation of HSC capacity compared to WT. Co-IP analysis revealed that BATF2 forms a complex with JUN to amplify pro-inflammatory signaling pathways including CCL5 during infection. Blockade of CCL5 receptors phenocopied Batf2 KO differentiation defects, whereas treatment with recombinant CCL5 was sufficient to rescue IFNγ-induced myeloid differentiation and recruit more immune cells to the spleen in Batf2 KO mice. By revealing the mechanism of BATF2-induced myeloid differentiation of HSCs, these studies elucidate potential therapeutic strategies to boost immunity while preserving HSC function during chronic infection., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hematopoietic stem and progenitor cells (HSPCs) are responsible for the production of all immune and blood cells in both steady state and emergency settings. The rates at which HSPCs divide and differentiate vary widely in accordance with both cell intrinsic and cell extrinsic factors. However, the kinetics of these events remain poorly understood. In prior work, we determined that the inflammatory cytokine interferon-γ (IFN-γ) induces HSPC division and differentiation. Here, we report that a subset of hematopoietic stem cells (HSCs) that express Fgd5 do not divide or differentiate in response to IFN-γ. This suggests that FGD5 marks a subset of HSCs that remains unperturbed during emergency hematopoiesis and is potentially a mechanism of preservation of the HSC compartment., Competing Interests: Conflict of Interest Disclosure The authors have declared that there are no conflicts of interest., (Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Clonal hematopoiesis of indeterminate potential (CHIP) describes a widespread expansion of genetically variant hematopoietic cells that increases exponentially with age and is associated with increased risks of cancers, cardiovascular disease, and other maladies. Here, we discuss how environmental contexts associated with CHIP, such as old age, infections, chemotherapy, or cigarette smoking, alter tissue microenvironments to facilitate the selection and expansion of specific CHIP mutant clones. Further, we consider major remaining gaps in knowledge, including intrinsic effects, clone size thresholds, and factors affecting clonal competition, that will determine future application of this field in transplant and preventive medicine., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Clonal hematopoiesis (CH) refers to the age-related expansion of specific clones in the blood system, and manifests from somatic mutations acquired in hematopoietic stem cells (HSCs). Most CH variants occur in the gene DNMT3A, but while DNMT3A-mutant CH becomes almost ubiquitous in aging humans, a unifying molecular mechanism to illuminate how DNMT3A-mutant HSCs outcompete their counterparts is lacking. Here, we used interferon gamma (IFNγ) as a model to study the mechanisms by which Dnmt3a mutations increase HSC fitness under hematopoietic stress. We found Dnmt3a-mutant HSCs resist IFNγ-mediated depletion, and IFNγ-signaling is required for clonal expansion of Dnmt3a-mutant HSCs in vivo. Mechanistically, DNA hypomethylation-associated overexpression of Txnip in Dnmt3a-mutant HSCs leads to p53 stabilization and upregulation of p21. This preserves the functional potential of Dnmt3a-mutant HSCs through increased quiescence and resistance to IFNγ-induced apoptosis. These data identify a previously undescribed mechanism to explain increased fitness of DNMT3A-mutant clones under hematopoietic stress., Significance: DNMT3A mutations are common variants in clonal hematopoiesis, and recurrent events in blood cancers. Yet the mechanisms by which these mutations provide hematopoietic stem cells a competitive advantage as a precursor to malignant transformation remain unclear. Here, we use inflammatory stress to uncover molecular mechanisms leading to this fitness advantage.See related commentary by De Dominici and DeGregori, p. 178. This article is highlighted in the In This Issue feature, p. 171., (©2022 American Association for Cancer Research.)

Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling. Using conditional knockout and chimeric mice, we found that the microbiota induced STAT1 signaling in non-myeloid hematopoietic cells to support hematopoiesis and that STAT1 signaling was specifically dependent on type I interferons (IFNs). Indeed, basal type I IFN signaling was reduced in hematopoietic progenitor cells with antibiotic treatment. In addition, we discovered that oral administration of a commensal-derived product, NOD1 ligand, rescues the hematopoietic defects induced by antibiotics in mice. Using metabolomics, we identified additional microbially produced candidates that can stimulate type I IFN signaling to potentially rescue the hematopoietic defects induced by antibiotics, including phosphatidylcholine and γ-glutamylalanine. Overall, our studies define a signaling pathway through which microbiota promotes normal hematopoiesis and identify microbial metabolites that may serve as therapeutic agents to ameliorate antibiotic-induced bone marrow suppression and cytopenia., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A Streptococcus (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5-7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50-60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis., Competing Interests: DM, BK, DL, AF, SP, KK No competing interests declared, (© 2022, Morales-Mantilla et al.)

Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a -/- and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a -/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a -/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a -/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration., Case Presentation: A 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation., Conclusions: The use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.

Interferons are an ancient and well-conserved group of inflammatory cytokines most famous for their role in viral immunity. A decade ago, we discovered that interferons also play an important role in the biology of hematopoietic stem cells (HSCs), which are responsible for lifelong blood production. Though we have learned a great deal about the role of interferons on HSC quiescence, differentiation, and self-renewal, there remains some controversy regarding how interferons impact these stem cells, with differing conclusions depending on experimental models and clinical context. Here, we review the contradictory roles of Type 1 and 2 interferons in hematopoiesis. Specifically, we highlight the roles of interferons in embryonic and adult hematopoiesis, along with short-term and long-term adaptive and maladaptive responses to inflammation. We discuss experimental challenges in the study of these powerful yet short-lived cytokines and strategies to address those challenges. We further review the contribution by interferons to disease states including bone marrow failure and aplastic anemia as well as their therapeutic use to treat myeloproliferative neoplasms and viral infections, including SARS-CoV2. Understanding the opposing effects of interferons on hematopoiesis will elucidate immune responses and bone marrow failure syndromes, and future therapeutic approaches for patients undergoing HSC transplantation or fighting infectious diseases and cancer., (Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Bone marrow suppression, including neutropenia, is a major adverse effect of prolonged antibiotic use that impairs the clinical care and outcomes of patients with serious infections. The mechanisms underlying antibiotic-mediated bone marrow suppression remain poorly understood, with initial evidence indicating that depletion of the intestinal microbiota is an important factor. Based on our earlier studies of blood and bone marrow changes in a mouse model of prolonged antibiotic administration, we studied whether changes in megakaryocytes or regulatory T cells (Tregs), two cell types that are critical in the maintenance of hematopoietic stem cells, contribute to antibiotic-mediated bone marrow suppression. Despite increased platelet numbers, megakaryocytes were unchanged in the bone marrow of antibiotic-treated mice; however, Tregs were found to be significantly depleted. Exogenous addition of Tregs was insufficient to rescue the function of bone marrow from antibiotic-treated mice in both colony formation and transplantation assays. These findings indicate that the intestinal microbiota support normal Treg development to protect healthy hematopoiesis, but that the restoration of Tregs alone is insufficient to restore normal bone marrow function.

During chronic infection, the inflammatory cytokine interferon gamma (IFNγ) damages hematopoietic stem cells (HSCs) by disrupting quiescence and promoting excessive terminal differentiation. However, the mechanism by which IFNγ hinders HSC quiescence remains undefined. Using intravital 3-dimensional microscopy, we find that IFNγ disrupts the normally close interaction between HSCs and CXCL12-abundant reticular (CAR) cells in the HSC niche. IFNγ stimulation increases expression of the cell surface protein BST2, which we find is required for IFNγ-dependent HSC relocalization and activation. IFNγ stimulation of HSCs increases their E-selectin binding by BST2 and homing to the bone marrow, which depends on E-selectin binding. Upon chronic infection, HSCs from mice lacking BST2 are more quiescent and more resistant to depletion than HSCs from wild-type mice. Overall, this study defines a critical mechanism by which IFNγ promotes niche relocalization and activation in response to inflammatory stimulation and identifies BST2 as a key regulator of HSC quiescence. VIDEO ABSTRACT., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) comprise the majority of mutations found in clonal hematopoiesis (CH), an age-related condition that was recently found to affect outcomes in patients undergoing hematopoietic stem cell transplant (HSCT). Recent studies have indicated that patients with CH have worse prognoses after HSCT, suggesting stress imposed by HSCT preconditioning agents may impact hematopoietic stem cell (HSC) dynamics in transplant recipients. In this study, we used a competitive transplantation mouse model to investigate how treatment with the common preconditioning agents 5-fluorouracil (5-FU) and busulfan (BU) affect the prevalence of Dnmt3a -/- HSCs and progenitor cells in competition with wild-type cells. We found that, though sufficient to deplete peripheral blood counts, 5-FU preconditioning did not significantly alter the frequency of Dnmt3a-null hematopoietic stem and progenitor cells (HSPCs) in mosaic mice. In contrast, mice treated with BU had a sevenfold decline in total bone marrow cells and an increase in Dnmt3a-null HSPCs that was detectable in peripheral blood. Indeed, even though all mosaic mice had a starting engraftment of ∼10%-40%, 85%-100% of HSPCs were Dnmt3a-null in four of seven mice after BU treatment, indicating these cells expand dramatically during recovery. Overall, these results suggest that individual preconditioning regimens have different effects on the expansion of Dnmt3a-mutant cells in patients with pre-existing CH. Thus, the presence of CH-associated mutants should be evaluated prior to selecting preconditioning regimens for HSCT., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. All rights reserved.)

Close to 14% of adults in the United States were reported to smoke cigarettes in 2018. The effects of cigarette smoke (CS) on lungs and cardiovascular diseases have been widely studied, however, the impact of CS in other tissues and organs such as blood and bone marrow remain incompletely defined. Finding the appropriate system to study the effects of CS in rodents can be prohibitively expensive and require the purchase of commercially available systems. Thus, we set out to build an affordable, reliable, and versatile system to study the pathologic effects of CS in mice. This whole-body inhalation exposure system (WBIS) set-up mimics the breathing and puffing of cigarettes by alternating exposure to CS and clean air. Here we show that this do-it-yourself (DIY) system induces airway inflammation and lung emphysema in mice after 4-months of cigarette smoke exposure. The effects of whole-body inhalation (WBI) of CS on hematopoietic stem and progenitor cells (HSPCs) in the bone marrow using this apparatus are also shown.

Clonal hematopoiesis (CH) has emerged as an important factor linked to adverse health conditions in the elderly. CH is characterized by an overrepresentation of genetically distinct hematopoietic stem cell clones in the peripheral blood. Whereas the genetic mutations that underlie CH have been closely scrutinized, relatively little attention has been paid to the environmental factors that may influence the emergence of one dominant stem cell clone. As there is huge individual variation in latency between acquisition of a genetic mutation and emergence of CH, environmental factors likely play a major role. Indeed, environmental stressors such as inflammation, chemotherapy, and metabolic syndromes are known to affect steady-state hematopoiesis. To date, epidemiologic studies point toward smoking and prior chemotherapy exposure as likely contributors to some forms of CH, though the impact of other environmental factors is also being investigated. Mechanistic studies in murine models indicate that the role of different environmental factors in CH emergence may be highly specific to the mutation that marks each stem cell clone. For instance, recent studies have found that clones with mutations in the PPM1D gene are more resistant to genotoxic stress induced by chemotherapy. These clones thus have a competitive advantage in the setting of chemotherapy, but not in other types of stress. Here we review currently available literature on the interplay between environment and the genetic landscapes in CH and highlight critical areas for future study. Improved understanding of the effects of environmental stress on emergence of CH with mutation-specific clarity will guide future efforts to provide preventive medicine to individuals with CH., (Copyright © 2019 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Inflammatory signals have emerged as critical regulators of hematopoietic stem cell (HSC) function. Specifically, HSCs are highly responsive to acute changes in systemic inflammation and this influences not only their division rate but also their lineage fate. Identifying how inflammation regulates HSCs and shapes the blood system is crucial to understanding the mechanisms underpinning these processes, as well as potential links between them., Recent Findings: A widening array of physiologic and pathologic processes involving heightened inflammation are now recognized to critically affect HSC biology and blood lineage production. Conditions documented to affect HSC function include not only acute and chronic infections but also autoinflammatory conditions, irradiation injury, and physiologic states such as aging and obesity., Summary: Recognizing the contexts during which inflammation affects primitive hematopoiesis is essential to improving our understanding of HSC biology and informing new therapeutic interventions against maladaptive hematopoiesis that occurs during inflammatory diseases, infections, and cancer-related disorders., Competing Interests: Conflict of InterestKatherine King, Daniel Hormaechea Agulla, and Duy Le declare that they have no conflict of interest., (© Springer Nature Switzerland AG 2020.)

TET2 is among the most frequently mutated genes in hematological malignancies, as well as in healthy individuals with clonal hematopoiesis. Inflammatory stress is known to promote the expansion of Tet2-deficient hematopoietic stem cells, as well as the initiation of pre-leukemic conditions. Infection is one of the most frequent complications in hematological malignancies and antibiotics are commonly used to suppress infection-induced inflammation, but their application in TET2 mutation-associated cancers remained underexplored. In this study, we discovered that Tet2 depletion led to aberrant expansion of myeloid cells, which was correlated with elevated serum levels of pro-inflammatory cytokines at the pre-malignant stage. Antibiotics treatment suppressed the growth of Tet2-deficient myeloid and lymphoid tumor cells in vivo. Transcriptomic profiling further revealed significant changes in the expression of genes involved in the TNF-α signaling and other immunomodulatory pathways in antibiotics-treated tumor cells. Pharmacological inhibition of TNF-α signaling partially attenuated Tet2-deficient tumor cell growth in vivo. Therefore, our findings establish the feasibility of targeting pro-inflammatory pathways to curtail TET2 inactivation-associated hematological malignancies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Suppurative thyroiditis is uncommon in the pediatric population and particularly rare to be caused by fungi. We present a case of Candida tropicalis thyroiditis in an adolescent male with acute lymphocytic leukemia that led to disseminated candidiasis, thyroid storm and eventual total thyroidectomy for source control.

Brodie abscess is a subacute hematogenous osteomyelitis characterized by intraosseous abscess formation. Treatment recommendations and clinical outcomes for this unusual infection are not well established. We report 15 cases of Brodie abscess in a 10-year retrospective review of pediatric patients at Texas Children's Hospital and describe their clinical presentation and outcomes.

As the intestinal microbiota has become better appreciated as necessary for maintenance of physiologic homeostasis and also as a modulator of disease processes, there has been a corresponding increase in manipulation of the microbiota in mouse models. While germ-free mouse models are generally considered to be the gold standard for studies of the microbiota, many investigators turn to antibiotics treatment models as a rapid, inexpensive, and accessible alternative. Here we describe and compare these two approaches, detailing advantages and disadvantages to both. Further, we detail what is known about the effects of antibiotics treatment on cell populations, cytokines, and organs, and clarify how this compares to germ-free models. Finally, we briefly describe recent findings regarding microbiota regulation of infectious diseases and other immunologic challenges by the microbiota, and highlight important future directions and considerations for the use of antibiotics treatment in manipulation of the microbiota.

Recent studies have revealed that the intestinal bacterial microbiome plays an important role in the regulation of hematopoiesis. A correlation between adverse hematologic effects and imbalance of the intestinal microbiome, or dysbiosis, is evident in several human conditions, such as inflammatory bowel disease, obesity, and, critically, in the setting of antibiotic exposure. Here we review the effects of gut dysbiosis on the hematological compartment and our current understanding of the mechanisms through which changes in the bacterial microbiome affect hematopoiesis., (© 2018 by The American Society of Hematology.)

Cellular quiescence is a key component of hematopoietic stem cell (HSC) homeostasis; therefore, a reliable method to measure HSC cell division is critical in many studies. However, measuring the proliferation rate of largely quiescent and rare populations of cells can be challenging. Bromo-deoxyuridine (BrdU) incorporation into replicating DNA is a commonly used and highly reproducible method to detect cell division history. Here, we describe a protocol for BrdU incorporation analysis in hematopoietic stem and progenitor cells that can provide a sensitive measure of cell division even in rare cell populations. In combination with flow cytometry, this method can be generalized to analyze other cell populations and other tissues as identified by cell surface markers.

Purpose of Review: Interferon-gamma (IFN-γ) is a pro-inflammatory cytokine that participates in the regulation of hematopoietic stem cells (HSC) during development and under homeostatic conditions. IFN-γ also plays a key pathogenic role in several diseases that affect hematopoiesis including aplastic anemia, hemophagocytic lymphohistiocytosis, and cirrhosis of the liver., Recent Findings: Studies have shown that increased IFN-γ negatively affects HSC homeostasis, skewing HSC towards differentiation over self-renewal and eventually causing exhaustion of the HSC compartment., Summary: Here, we explore the mechanisms by which IFN-γ regulates HSC in both normal and pathological conditions. We focus on the role of IFN-γ signaling in HSC fate decisions, and the transcriptional changes it elicits. Elucidating the mechanisms through which IFN-γ regulates HSCs may lead to new therapeutic options to prevent or treat adverse hematologic effects of the many diseases to which IFN-γ contributes., Competing Interests: Daniel E. Morales-Mantilla and Katherine Y. King declare that they have no conflict of interest.All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Inflammatory signals can activate hematopoietic stem cells (HSCs), but how HSCs regain quiescence after stress is unclear. In this issue of Cell Stem Cell, Chen et al. (2017) delineate an elegant histamine-dependent feedback mechanism through which myeloid bone marrow cells restore quiescence of myeloid-biased HSCs, with implications for blood disorders, aging, and immunity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

MicroRNA-22 (miR-22) is a highly conserved microRNA that can regulate cell proliferation, oncogenesis, and cell maturation, especially during stress. In hematopoietic stem cells (HSCs), miR-22 has been reported to be involved in the regulation of key self-renewal factors, including Tet2. Recent work demonstrates that miR-22 also participates in regulation of the interferon (IFN) response, and expression profiling studies suggest that it is variably expressed at different stages in erythroid differentiation. We thus hypothesized that miR-22 regulates maturation of erythroid progenitors during stress hematopoiesis through its interaction with IFN. We compared the blood and bone marrow of wild-type (WT) and miR-22-deficient mice at baseline and upon infectious challenge with systemic lymphochoriomeningitis (LCMV) virus. miR-22-deficient mice maintained platelet counts better than WT mice during infection, but they showed significantly reduced red blood cells and hemoglobin. Analysis of bone marrow progenitors demonstrated better overall survival and improved HSC homeostasis in infected miR-22-null mice compared with WT, which was attributable to a blunted IFN response to LCMV challenge in the miR-22-null mice. We found that miR-22 was expressed exclusively in stage II erythroid precursors and downregulated upon infection in WT mice. Our results indicate that miR-22 promotes the IFN response to viral infection and that it functions at baseline as a brake to slow erythroid differentiation and maintain adequate erythroid potential. Impaired regulation of erythrogenesis in the absence of miR-22 can lead to anemia during infection., (Copyright © 2017 ISEH – Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Bone marrow suppression is an adverse effect associated with many antibiotics, especially when administered for prolonged treatment courses. Recent advances in our understanding of steady-state hematopoiesis have allowed us to explore the effects of antibiotics on hematopoietic progenitors in detail using a murine model. Antibiotic-treated mice exhibited anemia, thrombocytosis, and leukopenia, with pronounced pan-lymphopenia as demonstrated by flow cytometric analysis of peripheral blood. Bone marrow progenitor analysis revealed depletion of hematopoietic stem cells and multipotent progenitors across all subtypes. Granulocytes and B cells were also diminished in the bone marrow, whereas the number of CD8 + T cells increased. Reductions in progenitor activity were not observed when cells were directly incubated with antibiotics, suggesting that these effects are indirect. Hematopoietic changes were associated with a significant contraction of the fecal microbiome and were partially rescued by fecal microbiota transfer. Further, mice raised in germ-free conditions had hematopoietic abnormalities similar to those seen in antibiotic-treated mice, and antibiotic therapy of germ-free mice caused no additional abnormalities. The effects of antibiotics were phenocopied in Stat1-deficient mice, with no additional suppression by antibiotics in these mice. We conclude that microbiome depletion as a result of broad-spectrum antibiotic treatment disrupts basal Stat1 signaling and alters T-cell homeostasis, leading to impaired progenitor maintenance and granulocyte maturation. Methods to preserve the microbiome may reduce the incidence of antibiotic-associated bone marrow suppression., (© 2017 by The American Society of Hematology.)

Chronic infections affect a third of the world's population and can cause bone marrow suppression, a severe condition that increases mortality from infection. To uncover the basis for infection-associated bone marrow suppression, we conducted repeated infection of WT mice with Mycobacterium avium. After 4-6 months, mice became pancytopenic. Their hematopoietic stem and progenitor cells (HSPCs) were severely depleted and displayed interferon gamma (IFN-γ) signaling-dependent defects in self-renewal. There was no evidence of increased HSPC mobilization or apoptosis. However, consistent with known effects of IFN-γ, transcriptome analysis pointed toward increased myeloid differentiation of HSPCs and revealed the transcription factor Batf2 as a potential mediator of IFN-γ-induced HSPC differentiation. Gain- and loss-of-function studies uncovered a role for Batf2 in myeloid differentiation in both murine and human systems. We thus demonstrate that chronic infection can deplete HSPCs and identify BATF2 as a mediator of infection-induced HSPC terminal differentiation., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hematopoietic stem cells (HSCs) reside in the bone marrow and are responsible for the lifetime maintenance of the blood and bone marrow, achieved through their differentiation into the myriad cellular components and their ability to generate additional stem cells via self-renewal. Identification of intrinsic and extrinsic factors that regulate how the HSC population is maintained over the lifespan of an organism, or those that trigger differentiation into mature hematopoietic cell types, are important goals for regenerative medicine. Recent studies have found that inflammatory signals play a role in the regulation of adult HSC homeostasis and tonic innate immune signals influence HSC development during embryogenesis. Additionally, dysregulation of inflammatory cytokines, and the consequent impact of this on hematopoietic progenitors, may be a contributing factor to the hematopoietic defects that occur during aging and in patients with bone marrow failure syndromes or blood cancers. To update recent findings on this topic, the International Society for Experimental Hematology (ISEH) organized a webinar entitled "The Role of Inflammatory Signals in Embryonic HSC Development and Adult HSC Function," which we summarize here., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Heterozygous mutations in the transcriptional regulator GATA-2 associate with multilineage immunodeficiency, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The majority of these mutations localize in the zinc finger (ZnF) domains, which mediate GATA-2 DNA binding. Deregulated hematopoiesis with GATA-2 mutation frequently develops in adulthood, yet GATA-2 function in the bone marrow remains unresolved. To investigate this, we conditionally deleted the GATA-2 C-terminal ZnF (C-ZnF) coding sequences in adult mice. Upon Gata2 C-ZnF deletion, we observed rapid peripheral cytopenia, bone marrow failure, and decreased c-Kit expression on hematopoietic progenitors. Transplant studies indicated GATA-2 has a cell-autonomous role in bone marrow hematopoiesis. Moreover, myeloid lineage populations were particularly sensitive to Gata2 hemizygosity, while molecular assays indicated GATA-2 regulates c-Kit expression in multilineage progenitor cells. Enforced c-Kit expression in Gata2 C-ZnF-deficient hematopoietic progenitors enhanced myeloid colony activity, suggesting GATA-2 sustains myelopoiesis via a cell intrinsic role involving maintenance of c-Kit expression. Our results provide insight into mechanisms regulating hematopoiesis in bone marrow and may contribute to a better understanding of immunodeficiency and bone marrow failure associated with GATA-2 mutation., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Interferon α (IFNα) is used clinically to restore polyclonal hematopoiesis in patients with the myeloproliferative neoplasms polycythemia vera and essential thrombocythemia and to improve chemosensitivity in chronic myeloid leukemia patients. However, the mechanisms by which IFNα affects disease-initiating hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. Although IFNα has been found to transiently impair quiescence of murine hematopoietic stem cells, its effects on human HSPCs have not been studied in vivo. Here, we compared bone marrow serially obtained from patients with myeloproliferative neoplasms before and during pegylated IFNα treatment against marrow serially obtained from patients on hydroxyurea. The percentage of HSPCs actively undergoing cell cycle was increased after pegylated IFNα treatment in a majority of patients compared with hydroxyurea-treated controls, suggesting that IFNα promotes cell division. Furthermore, transcriptional profiling revealed that cell cycle-associated genes were induced, whereas genes involved in HSPC quiescence were repressed during IFNα treatment. Compared with hydroxyurea-treated controls, pegylated IFNα-treated patients had similar numbers of HSPCs, but increased numbers of hematopoietic progenitors as determined by colony formation assay, indicating an increase in myeloid proliferation/differentiation. These effects occurred regardless of JAK2 mutational status. Together, these data provide the first in vivo evidence that pegylated IFNα promotes cell division and differentiation of human HSPCs., (Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)