A5014950391- Single-cell and spatial transcriptomics
- Hematopoietic Stem Cell Transplantation
- Acute Myeloid Leukemia Research
- Immune cells in cancer
- Immune Cell Function and Interaction
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Virus-based gene therapy research
- Mesenchymal stem cell research
- Zebrafish Biomedical Research Applications
- Immune responses and vaccinations
- Cancer Genomics and Diagnostics
- RNA Interference and Gene Delivery
- Pregnancy and preeclampsia studies
- Chronic Myeloid Leukemia Treatments
- Erythrocyte Function and Pathophysiology
- Xenotransplantation and immune response
- Eosinophilic Disorders and Syndromes
- Lymphoma Diagnosis and Treatment
- Immunodeficiency and Autoimmune Disorders
- IL-33, ST2, and ILC Pathways
- Neural Networks and Applications
- MicroRNA in disease regulation
- Extracellular vesicles in disease
- Platelet Disorders and Treatments
University of Cambridge
2016-2024
Medical Research Council
2022-2024
Wellcome/MRC Cambridge Stem Cell Institute
2016-2024
Stem Cell Institute
2022-2023
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer 4–6 but the reason for such abrupt functional decline after 70 years age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies haematopoietic cells across 10 subjects 0 to 81 age. Haematopoietic stem or multipotent progenitors (HSC/MPPs) accumulated a mean 17 mutations per year birth lost 30 base pairs...
Abstract Capturing where and how multipotency is lost crucial to understand blood formation controlled. Blood lineage specification currently thought occur downstream of multipotent haematopoietic stem cells (HSC). Here we show that, in human, the first restriction events within CD19 − CD34 + CD38 CD45RA CD49f CD90 (49f ) HSC compartment generate myelo-lymphoid committed with no erythroid differentiation capacity. At single-cell resolution, observe a continuous but polarised organisation 49f...
Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress disease but remain ill-defined. Although nonmobilized peripheral (PB) is routinely sampled for clinical management, diagnosis monitoring potential of PB HSPCs untapped, as no healthy HSPC baseline has been reported. Here we comprehensively delineate human extramedullary compartments comparing spleen, PB, mobilized BM using single-cell RNA-sequencing and/or functional...
Loss of long-term hematopoietic stem cell (LT-HSC) function ex vivo hampers the success clinical protocols that rely on culture. However, kinetics and mechanisms through which this occurs remain incompletely characterized. In study, time-resolved single-cell RNA sequencing, matched in functional analysis, use a reversible vitro system early G1 arrest, we defined sequence transcriptional events occur during first division human LT-HSCs. We demonstrated sharpest loss LT-HSC repopulation...
Abstract The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. Although this process is thought to be spatially restricted the yolk sac in mouse, humans, it remains poorly understood. Human foetal placental macrophages, or Hofbauer cells (HBC), arise haematopoietic wave ~18 days post conception and lack expression of human leukocyte antigen (HLA) class II. Here, we identify a population (PEMPs) early placenta...
Hematopoietic stem cells (HSCs) accumulate somatic mutations over time, some conferring a fitness advantage that can lead to clonal hematopoiesis (CH). Mutations in DNMT3A , particularly at hotspot R882, are the most prevalent CH and carry an increased risk of acute myeloid leukemia (AML). Although R882 linked global DNA hypomethylation, mechanisms underlying their selective remain unclear. Here, we show Dnmt3a-R882H mutant HSCs exhibit resilience under inflammatory genotoxic stress. During...
Abstract Age-related change in human haematopoiesis causes reduced regenerative capacity 1 , cytopenias 2 immune dysfunction 3 and increased risk of blood cancer. The cellular alterations that underpin the abruptness this functional decline after age 70 years remain elusive. We sequenced 3579 genomes from single-cell-derived colonies haematopoietic stem cell/multipotent progenitors (HSC/MPPs) across 10 haematologically normal subjects aged 0-81 years. HSC/MPPs accumulated 17 mutations/year...
Abstract Normal and malignant hematopoietic stem cells (HSCs) are controlled by extracellular cues including cytokine signalling through the JAK/STAT pathway. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: while reduced multi-lineage repopulation self-renewal commonly associated with overproliferation exhaustion, they instead cell-cycle progression increased differentiation in HSCs. Mechanistic studies unphosphorylated-STAT5 (uSTAT5) contributes to this phenotype...
Key Points CLL increases the pool of ST-HSCs in peripheral blood. Differentiation CLL-derived blood HSPCs is skewed toward myeloid lineage.
Summary Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs), yet remains poorly defined humans. Using single cell transcriptome profiling ~133,000 ~65,000 skin kidney cells, we identify repertoire blood immune cells first early second trimesters development. From this data, infer trajectories from HSC/MPPs, evaluate impact tissue microenvironment on We predict coupling mast with...
Abstract Recent lineage tracing single-cell techniques (LT-scSeq), e.g., the Lineage And RNA RecoverY (LARRY) barcoding system, have enabled clonally resolved interpretation of differentiation trajectories. However, heterogeneity clone-specific kinetics remains understudied, both quantitatively and in terms interpretability, thus limiting power bar-coding systems to unravel how heterogeneous stem cell clones drive overall population dynamics. Here, we present CLADES, a NeuralODE-based...
Abstract The earliest macrophages are generated during embryonic development from erythro-myeloid progenitors (EMPs) via primitive haematopoiesis. This process is still poorly understood in humans but generally thought to be spatially restricted the yolk sac. Human fetal placental macrophages, Hofbauer cells (HBC), arise haematopoietic wave, yet unlikely sac derived as they appear prior vascularisation. Here we identify a population of (PEMPs) early human placenta that give rise HBC. PEMP...
Abstract Loss of long-term haematopoietic stem cell function (LT-HSC) hampers the success ex vivo HSC gene therapy and expansion procedures, but kinetics mechanisms by which this occurs remain incompletely characterized. Here through time-resolved scRNA-Seq, matched in functional analysis use a reversible vitro system early G 1 arrest, we define sequence transcriptional events occurring during first division human LT-HSCs. We demonstrate that contrary to current assumptions, loss...
Hematopoietic stem cells (HSCs) are defined by their lifelong ability to produce all blood cell types. This is operationally tested transplanting populations containing HSCs into syngeneic or immunocompromised mice. The size and multilineage composition of the graft then measured over time, usually flow cytometry. Classically, a population injected circulation animal, after which home bone marrow, where they lodge begin production. Alternatively, and/or progenitor (HSPCs) can be placed...
Hematopoietic stem cells (HSCs) are defined by their lifelong ability to produce all blood cell types. This is operationally tested transplanting populations containing HSCs into syngeneic or immunocompromised mice. The size and multilineage composition of the graft then measured over time, usually flow cytometry. Classically, a population injected circulation animal, after which home bone marrow, where they lodge begin production. Alternatively, and/or progenitor (HSPCs) can be placed...