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17 recordsLinked to original sources
PubMed2026

Mov10 mitigates hematopoietic stem cell exhaustion under stress by modulating the Camp-mediated inflammatory pathway.

The integrity of hematopoietic stem cell (HSC) function is crucial for robust hematopoietic regeneration following stress. Inflammatory responses are pivotal drivers of HSC stress response, yet the precise modulation of inflammatory pathways remains incompletely defined. In this study, we identify the RNA helicase Mov10 as a negative regulator of stress-induced inflammatory pathways in HSC. Our study indicates that Mov10, which is critically required for HSC maintenance, is highly expressed in HSC, and its loss adversely affects HSC fitness and survival during hematopoietic stress induced by bone marrow transplantation and irradiation (IR). Mechanistically, Mov10 mitigates excessive inflammatory activation to sustain HSC functional integrity during hematopoietic stress, primarily by enhancing the translation of CAMP, which inhibits the interaction between TNF-α and its receptor TNFR1 and suppresses NF-κB activation. Overall, our results imply that Mov10 plays a critical role in averting functional failure of hematopoiesis under stress, presenting viable paths for the therapeutic intervention of relevant diseases.

Camp↗
PubMed1979

Structural identity of the pluripotential hemopoietic stem cell.

A review is presented of the experiments that resulted in the identification of a specific morphologic entity representing the pluripotential hemopoietic stem cell (HSC) in mouse bone marrow. This entity was subsequently discovered in concentrated HSC preparations from bone marrow of rats, monkeys, and humans. In the mouse, a set of physical parameters (of the HSC) has been collected which agree with its morphologic description. It was also shown that these physical properties, and a number of cell surface properties, do not enable a distinction between HSC and its immediate descendants, the G/M CFU 1 and the E-BFU. The factors that stimulate proliferation of these three cell types have been isolated from human leukocyte conditioned medium and mouse spleen conditioned medium and were partly purified and characterized. The information at present indicates that the three cell types respond to closely related, if not identical, factors. Direct counts of HSC in electron microscopic preparations of density gradient fractions of different enrichment have been compared with HSC values computed from spleen colony counts and f factors for rat and mouse marrow. A high degree of correlation was found between the two types of observations. The slopes of the regression lines for mouse marrow fractions, for concentrates of normal rat marrow, and for concentrates of cycling rat marrow were the same, namely, 0.5. The deviation of this value from the expected value of 1.0 is probably not due to the use of erroneous f values. It is proposed that the observed discrepancy may be due to heterogeneity of spleen colony forming cells, in that a proportion of them may not be pluripotential.

Animals↗
PubMed1977

Nature of the delayed graft-versus-host reactivity of fetal liver cell transplants in mice.

Experiments were designed to determine which actual differences in the cellular composition between fetal liver and bone marrow account for the distinct types of graft-versus-host (GvH) disease. The assay of reactive lymphocytes (by in vitro mitogenic stimulation) in fetal liver transplants in mice, the purification of hemopoietic stem cells (HSC) of the transplants, and the quantitation of HSC numbers in the grafts traced the basis for the distinctly weak type of GvH disease after fetal liver cell grafts. It was found that transplantation of purified HSC concentrates did not modify the severity of GvH mortality. The moderate character of the delayed GvH disease was shown to depend on the presence of an HSC population in fetal liver with different qualities and not on numerical differences between the HSC in fetal liver and bone marrow. Data collected also demonstrated that when GvH disease occurred in the recipients of transplants of fetal liver, it shared the characteristic histologic features of the bone marrow GvH syndrome. The recovery of mitogen responsiveness of spleen cells may have been delayed in fetal liver allotransplantation as compared to syngeneic grafting. By supportive infusion of lymphoid cells, it was suggested that the immunodeficiency coinciding with GvH disease represented a secondary manifestation of the disease rather than a primary impairment in lymphoid differentiation.

Animals↗
PubMed2025

Duganella hordei sp. nov., Duganella caerulea sp. nov., and Duganella rhizosphaerae sp. nov., isolated from barley rhizosphere.

Duganella sp. strains R1T, R57T, and R64T, isolated from barley roots in Japan, are Gram-stain-negative, motile, rod-shaped bacteria. Duganella species abundantly colonized barley roots. Strains R1T, R57T, and R64T were capable of growth at 4 °C, suggesting adaptation to colonize winter barley roots. Strains R57T and R64T formed purple colonies, indicating violacein production, while strain R1T did not. Based on 16S rRNA gene sequence similarities, strains R1T, R57T, and R64T were most closely related to D. violaceipulchra HSC-15S17T (99.10%), D. vulcania FT81WT (99.45%), and D. violaceipulchra HSC-15S17T (99.86%), respectively. Their genome sizes ranged from 7.05 to 7.38 Mbp, and their genomic G+C contents were 64.2-64.7%. The average nucleotide identity and digital DNA-DNA hybridization values between R1T and D. violaceipulchra HSC-15S17T, R57T and D. vulcania FT81WT, R64T and D. violaceipulchra HSC-15S17T were 86.0% and 33.2%, 95.7% and 67.9%, and 92.7% and 52.6%, respectively. Their fatty acids were predominantly composed of C16:0, C17:0 cyclo, and summed feature 3 (C16:1 ω7c and/or C16:1 ω6c). Based on their distinct genetic and phenotypic characteristics, and supported by chemotaxonomic analyses, we propose that strains R1T, R57T, and R64T represent novel species within the Duganella genus, for which the names Duganella hordei (type strain R1T = NBRC 115982 T = DSM 115069 T), Duganella caerulea (type strain R57T = NBRC 115983 T = DSM 115070 T), and Duganella rhizosphaerae (type strain R64T = NBRC 115984 T = DSM 115071 T) are proposed.

Hordeum↗
PubMed2025

BCLAF1 restrains stress responses in hematopoietic stem cells to support expansion and repopulation.

Hematopoietic stem cells (HSCs) rapidly expand during fetal development and after stress. Here, we identify B-cell lymphoma-2-associated factor 1 (BCLAF1) as a regulator of HSC repopulation activity, with roles in the expansion of fetal HSCs and hematopoietic reconstitution after stem cell transplantation. Using mice with hematopoietic-specific and inducible deletion of Bclaf1, we find that BCLAF1 promotes fetal HSC development but is dispensable for the maintenance of adult HSCs at steady state. Loss of BCLAF1 in either fetal or adult HSCs significantly impairs their self-renewal and multilineage reconstitution activity after stem cell transplantation. Single-cell RNA sequencing of fetal hematopoietic progenitors reveals that loss of BCLAF1 reduces long-term HSCs and restrains the expression of stress response genes. BCLAF1 associates with chromatin throughout the genome of fetal and adult hematopoietic cells, likely through indirect mechanisms, to regulate transcriptional programs. These results establish a novel function for the transcriptional regulator BCLAF1 in limiting stress responses in HSCs, thereby preserving HSC development during embryogenesis and repopulation function after stem cell transplant.

Hematopoietic Stem Cells↗
PubMed2025

Differentiation latency and dormancy signatures define fetal liver hematopoietic stem cells at single-cell resolution.

Decoding the mechanisms governing the self-renewal of hematopoietic stem cells (HSCs) during their expansion in the fetal liver (FL) could unlock novel therapeutic strategies to expand transplantable HSCs, a long-standing challenge. To explore intrinsic and extrinsic regulation of FL-HSC self-renewal at single-cell resolution, we engineered a culture platform replicating the FL endothelial niche that supports the amplification of serially engraftable HSCs. Leveraging this platform together with single-cell index flow cytometry, live imaging, transplantation assays, and single-cell RNA sequencing, we demonstrate that differentiation latency, cell-division symmetry, and transcriptional signatures of biosynthetic dormancy are distinguishing properties of rare FL-HSCs capable of serial multilineage hematopoietic reconstitution. Our findings support a paradigm in which intrinsic programs and niche-derived signals together facilitate the symmetric self-renewal of FL-HSCs while delaying their active participation in hematopoiesis. Our study also provides a resource for future investigations into intrinsic and extrinsic signaling pathways governing FL-HSC self-renewal.

Hematopoietic Stem Cells↗
PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗
PubMed2025

Non-canonical functions of DNMT3A in hematopoietic stem cells regulate telomerase activity and genome integrity.

DNMT3A is a critical regulator of hematopoietic stem cell (HSC) fate decisions and the most recurrently mutated gene in human clonal hematopoiesis (CH). DNMT3A is described as a DNA methyltransferase enzyme, but cells with DNMT3A loss of function show minor changes in DNA methylation that do not correlate with altered gene expression. To explore the possibility that Dnmt3a has DNA-methylation-independent functions in HSCs, we created an allelic series of mice with varying levels of DNA-methylation-impaired Dnmt3a. Clonal expansion of Dnmt3a-deficient HSCs was rescued by Dnmt3a proteins lacking DNA methylation capacity, suggesting that Dnmt3a has important non-canonical functions in HSCs. Dnmt3a-null HSCs can be transplanted indefinitely, implying the ability to circumvent mechanisms that limit the replicative lifespan of HSCs, such as telomere shortening. Dnmt3a-null HSCs show increased telomerase activity and sustain telomere length over serial transplantation, revealing a previously unidentified role for DNMT3A mutations in regulating HSC longevity that is unrelated to DNA methylation function.

Animals↗
PubMed2024

Introducing a hemoglobin G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.

Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrate correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We show successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements in the derived red blood cells. After ex vivo transduction of HSCs from an SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without any noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires a single non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach holds potential for scalable applications in resource-limiting regions where SCD is prevalent.

Animals↗
PubMed2026

Translational regulation of Sf1 integrates alternative splicing and hematopoietic stem cell fate.

The transition of hematopoietic stem cells (HSCs) from quiescence to lineage commitment requires precise posttranscriptional control, yet the contribution of mRNA isoform regulation remains poorly defined. Here, we identify a translationally controlled splicing program that contributes to HSC fate decisions. Using activity-based signatures of 305 splicing regulators, we uncover widespread posttranscriptional modulation of the spliceosome in stem and progenitor cells. The branch point recognition factor Sf1 emerges as a key node, regulated by a conserved structured 5' untranslated region (UTR) that cooperates with the RNA-binding protein Igf2bp2 to control its translation. Disrupting this cis-trans module reduces Sf1 protein synthesis and skews differentiation toward stem and erythroid programs. Mechanistically, Sf1-dependent alternative splicing remodels 5' UTRs of hematopoietic and DNA damage response genes, altering their translation and modulating DNA damage resolution. Together, these findings reveal an unrecognized translational layer controlling spliceosome activity and link RNA regulons, alternative splicing, and HSC fate determination.

Alternative Splicing↗
PubMed2026

The prognostic value and molecular mechanisms of Porphyromonas gingivalis infection-associated differentially expressed genes in oral squamous cell carcinoma.

BACKGROUND: Increasing evidence suggests that Porphyromonas gingivalis (Pg) is associated with oral squamous cell carcinoma (OSCC) development and progression. This study aimed to identify Pg-associated genes with prognostic relevance in OSCC through integrated bioinformatics analysis. METHODS: OSCC-related differentially expressed genes (DEGs) were identified from the The Cancer Genome Atlas (TCGA)-OSCC cohort and intersected with Pg supernatant-associated DEGs from GSE192887. Raw count data were analyzed with DESeq2, whereas transcripts per million (TPM)-transformed expression values were used for downstream visualization and model construction. Weighted gene co-expression network analysis (WGCNA), univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression, and multivariable Cox modeling were used to develop a seven-gene prognostic signature, which was externally evaluated in GSE41613. Additional analyses examined treatment-associated expression changes in the seven model genes, pairwise correlations among the model genes, and correlations between Pg supernatant-associated differentially expressed gene (PgSDEG)-derived module eigengenes and immune-cell fractions. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed in eight paired OSCC and adjacent non-tumor tissues and in supplemented-brain heart infusion (BHI) vehicle-control and Pg culture-supernatant-treated HOK, HSC-3, and CAL-27 cells. RESULTS: A prognostic signature comprising CXCL8, GAST, HBQ1, PADI3, STC1, TEX19, and TMEM92 was established. The signature showed limited-to-moderate discrimination in the TCGA training cohort, with 1-, 3-, and 5-year areas under the curve (AUCs) of 0.68, 0.69, and 0.69, respectively, and limited discrimination in the GSE41613 external cohort (AUCs: 0.66, 0.67, and 0.61). Kaplan-Meier analysis showed poorer survival in the high-risk group in both cohorts. The GSE192887 analysis showed significant treatment-associated expression changes in all seven genes after Pg culture-supernatant exposure. In paired tissues, CXCL8 and TMEM92 were significantly higher in OSCC tissues, whereas STC1 was not significant after Holm correction. In CAL-27 cells, CXCL8, STC1, and TMEM92 increased significantly after culture-supernatant treatment, whereas the corresponding comparisons were not significant in HOK or HSC-3 cells after adjustment. CONCLUSIONS: This study developed a seven-gene Pg-associated prognostic signature for OSCC and provided complementary transcriptomic, immune-correlation, tissue, and cell-based evidence that placed the signature in biological context. The model showed limited-to-moderate discrimination and is not ready for clinical use. The enrichment, gene-correlation, and immune-correlation findings are hypothesis-generating rather than mechanistic evidence. Further independent validation and dedicated functional studies are required.

Oral squamous cell carcinoma (OSCC)↗
PubMed2026

Single-cell vector copy number analysis of phenotypically defined long-term hematopoietic stem cells for gene therapy safety assessment.

Hematopoietic stem cell (HSC)-based gene therapy has emerged as a transformative approach for the treatment of genetic diseases; however, accurate evaluation of vector copy number (VCN) remains critical for ensuring safety. Conventional bulk VCN assays, including quantitative PCR (qPCR) and droplet digital PCR (ddPCR), do not resolve clonal heterogeneity and cannot identify rare high-VCN cells that may contribute disproportionately to insertional mutagenesis risk. Here, we developed an accessible single-cell VCN profiling method by combining fluorescence-activated cell sorting (FACS) of phenotypically defined long-term HSCs (Lineage- CD34+ CD38- CD90+ CD45RA- cells) with whole-genome amplification followed by conventional qPCR. This approach enabled resolution of VCN distributions at single-cell level using standard laboratory techniques. Notably, single-cell analysis revealed a high VCN tail that bulk VCN analysis could not resolve. Furthermore, in a humanized mouse transplantation model, single-cell VCN profiling demonstrated that overall VCN distributions could be analyzed after engraftment, although inter-donor and inter-mouse variability was observed. Collectively, this method provides a rapid, cost-effective, and phenotypically resolved strategy for assessing VCN heterogeneity in gene-modified HSCs. Single-cell VCN profiling offers complementary insights beyond conventional bulk assays and may enhance preclinical safety evaluation of gene and cell therapy products.

lentiviral vector↗
PubMed2026

Type 1 interferon perturbates clonal competition by reshaping human blood development.

Inflammation accelerates evolutionary dynamics of hematopoietic stem cells (HSCs) in clonal hematopoiesis and myeloid neoplasms. We studied HSCs, progenitors and immune cells from patients with myeloproliferative neoplasms at baseline and following interferon-α (IFNα) treatment, the only therapy to deplete mutated stem cells. We deployed single-cell multiomics methods that distinguish the IFNα effects on mutated stem cells from the admixed wild-type HSCs, with respect to their differentiation, transcriptomes, immunophenotypes and chromatin accessibility. IFNα simultaneously activated HSCs into two polarized states: a lymphoid progenitor expansion associated with an anti-inflammatory state and an inflammatory myeloid progenitor state derived from HSCs. The augmented lymphoid differentiation balanced the typical myeloproliferative-neoplasm-induced myeloid bias, associated with normalized blood counts. Somatic mutations modified the effects of IFNα on HSC differentiation and cell cycle entry rates. Clonal fitness upon IFNα exposure was due to resistance of CALR- or JAK2-mutated stem cells to differentiate into inflammatory myeloid progenitors.

Journal Article↗
PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗
PubMed2024

Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis.

Hematopoietic stem cells (HSCs) and erythropoiesis are activated during pregnancy and after bleeding by the derepression of retrotransposons, including endogenous retroviruses and long interspersed nuclear elements. Retrotransposon transcription activates the innate immune sensors cyclic guanosine 3',5'-monophosphate-adenosine 5'-monophosphate synthase (cGAS) and stimulator of interferon (IFN) genes (STING), which induce IFN and IFN-regulated genes in HSCs, increasing HSC division and erythropoiesis. Inhibition of reverse transcriptase or deficiency for cGAS or STING had little or no effect on hematopoiesis in nonpregnant mice but depleted HSCs and erythroid progenitors in pregnant mice, reducing red blood cell counts. Retrotransposons and IFN-regulated genes were also induced in mouse HSCs after serial bleeding and, in human HSCs, during pregnancy. Reverse transcriptase inhibitor use was associated with anemia in pregnant but not in nonpregnant people, suggesting conservation of these mechanisms from mice to humans.

Animals↗
PubMed2026

Endothelial MHC expression is required to initiate T cell-mediated rejection of 3D-printed skin grafts.

Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.

Animals↗
PubMed2026

Ex vivo long-term expansion of human hematopoietic stem and progenitor cells as a tool for modeling vector integration sites and clonality.

BACKGROUND: Gene therapy (GT) using retroviral vectors (RVs) is efficacious in treating monogenic diseases. However, there is an inherent risk for severe adverse effects due to insertional mutagenesis. Preclinical safety assessment and patient monitoring are inevitable in GT. To assess the genotoxic risk of novel RV vectors, mainly murine hematopoietic stem and progenitor cells (HPSCs) are routinely used, because human HSPCs cannot be immortalized in vitro using mutagenic vectors. In this study, we aim to identify early signs of clonal outgrowth by performing integration site analyses (ISA). METHODS: The small molecules A83-01, pomalidomide, and UM171 (APU) were used for the ex vivo expansion, lentiviral transduction, and long-term cultivation of umbilical cord blood-derived HSPCs. We determined the influence of APU on the stemness of HSPCs and their differentiation capacity via single-cell RNA sequencing (scRNA seq) and in xenotransplantation studies. To track vector insertion site dynamics, we transduced 7-day expanded HSPCs with a mutagenic or a safer RV. ISA was conducted in human HSPCs over a 5-week cultivation in vitro and compared to the bone marrow of xenotransplanted mice to assess clonal skewings. RESULTS: APU supported the expansion of CD34+CD38-CD45RA-CD90+EPCR+ HSPCs. scRNA seq confirmed the enrichment of HSC signature genes in APU-expanded HSPCs compared to the clinically used medium SFT3 (SCF, FLT3-L, TPO, IL-3). After RV transduction, APU still maintained around 30% of CD34+ cells for 5 more weeks. Without the compounds, already 2 weeks post-transduction, less than 10% of cells were CD34+. The long-term culture allowed the detection of high-risk integrations of the mutagenic SIN-LV.SF in MEIS1 or SUSD6 due to their increasing abundance over time. Bone marrow of xenotransplanted mice was less clonal but did not support the outgrowth of insertional mutants. Overall, APU increased clonal diversity. CONCLUSIONS: Our findings propose that long-term cultivation of transduced HSPC in APU allows for outgrowth of clonal integration sites. The decrease of clonality has been observed in gene therapy patient's years after treatment. Thus, the in vitro model could be used to develop novel human HSPC-based genotoxicity assays that predict insertional mutagenesis, in addition to existing preclinical biosafety assays.

Humans↗