A5029813665- Hematopoietic Stem Cell Transplantation
- Single-cell and spatial transcriptomics
- Acute Myeloid Leukemia Research
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Mesenchymal stem cell research
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Kruppel-like factors research
- Chronic Myeloid Leukemia Treatments
- Intraocular Surgery and Lenses
- Cytokine Signaling Pathways and Interactions
- CRISPR and Genetic Engineering
- Epigenetics and DNA Methylation
- Pluripotent Stem Cells Research
- Multiple Myeloma Research and Treatments
- Corneal surgery and disorders
- CAR-T cell therapy research
- Erythrocyte Function and Pathophysiology
- Immune cells in cancer
- Zebrafish Biomedical Research Applications
- MicroRNA in disease regulation
- Pancreatic function and diabetes
- Prenatal Screening and Diagnostics
- Blood disorders and treatments
University of York
2016-2025
Wellcome/MRC Cambridge Stem Cell Institute
2015-2024
University of Cambridge
2015-2024
Hull York Medical School
2024
Leeds Teaching Hospitals NHS Trust
2024
Leeds General Infirmary
2024
Creative Commons
2021-2022
Biomedical Research Institute
2021
Boston Biomedical Research Institute
2021
Alex's Lemonade Stand Foundation
2020
Somatic mutations in the Janus kinase 2 gene (JAK2) occur many myeloproliferative neoplasms, but molecular pathogenesis of neoplasms with nonmutated JAK2 is obscure, and diagnosis these remains a challenge.
Cancers result from the accumulation of somatic mutations, and their properties are thought to reflect sum these mutations. However, little is known about effect order in which mutations acquired.We determined mutation patients with myeloproliferative neoplasms by genotyping hematopoietic colonies or means next-generation sequencing. Stem cells progenitor were isolated study on mature immature cells.The age at a patient presented neoplasm, acquisition JAK2 V617F homozygosity, balance...
Heterogeneity within the self-renewal durability of adult hematopoietic stem cells (HSCs) challenges our understanding molecular framework underlying HSC function. Gene expression studies have been hampered by presence multiple subtypes and contaminating non-HSCs in bulk populations. To gain deeper insight into gene program murine HSCs, we combined single-cell functional assays with flow cytometric index sorting assays. Through bioinformatic integration these datasets, designed an unbiased...
The regulation of HSC proliferation and engraftment the BM is an important but poorly understood process, particularly during ontogeny. Here we show that in mice, all HSCs are cycling until 3 weeks after birth. Then, within 1 week, most became quiescent. Prior to 4 age, proliferating with long-term multilineage repopulating activity displayed defect when transiting S/G2/M. During these cell cycle phases, their expression CXC chemokine ligand 12 (CXCL12; also referred as stromal cell–derived...
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...
Hematopoietic stem cells (HSCs) execute self-renewal divisions throughout fetal and adult life, although some of their properties do alter. Here we analyzed the magnitude timing changes in differentiated cell outputs transplanted HSCs obtained from different sources during development. We also assessed expression several "stem cell" genes corresponding populations highly purified HSCs. Fetal displayed marked differences self-renewal, output, gene properties, with persistence a phenotype...
The hematopoietic system produces a large number of highly specialized cell types that are derived through hierarchical differentiation process from common stem population. miRNAs critical players in orchestrating this differentiation. Here, we report the development and application high-throughput microfluidic real-time quantitative PCR (RT-qPCR) approach for generating global miRNA profiles 27 phenotypically distinct populations isolated normal adult mouse tissues. A total 80,000 RT-qPCR...
Heterozygous somatic mutations affecting the spliceosome gene SF3B1 drive age-related clonal hematopoiesis, myelodysplastic syndromes (MDS) and other neoplasms. To study their role in such disorders, we generated knock-in mice with hematopoietic-specific expression of Sf3b1-K700E, commonest type mutation MDS. Sf3b1K700E/+ animals had impaired erythropoiesis progressive anemia without ringed sideroblasts, as well reduced hematopoietic stem cell numbers host-repopulating fitness. understand...
Adult blood contains a mixture of mature cell types, each with specialized functions. Single hematopoietic stem cells (HSCs) have been functionally shown to generate all types for the lifetime organism. Differentiation HSCs toward alternative lineages must be balanced at population level by fate decisions made individual cells. Transcription factors play key role in regulating these and operate within organized regulatory programs that can modeled as transcriptional networks. As...
Aging of the hematopoietic stem cell (HSC) compartment is characterized by lineage bias and reduced function, molecular basis which largely unknown. Using single-cell transcriptomics, we identified a distinct subpopulation old HSCs carrying p53 signature indicative decline alongside pro-proliferative JAK/STAT signaling. To investigate relationship between signaling, challenged with constitutively active form JAK2 (V617F) observed an expansion p53-positive in mice. Our results reveal cellular...
Abstract The lymphocyte genome is prone to many threats, including programmed mutation during differentiation 1 , antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell cultures, we sequenced whole genomes from 717 normal naive memory B T cells haematopoietic stem cells. All subsets carried more point mutations structural variants than cells, with higher burdens accumulating at a rate throughout life. Off-target...
Early career researchers (ECRs) are important stakeholders leading efforts to catalyze systemic change in research culture and practice. Here, we summarize the outputs from a virtual unconventional conference (unconference), which brought together 54 invited experts 20 countries with extensive experience ECR initiatives designed improve practice of science. Together, drafted 2 sets recommendations for (1) ECRs directly involved or activities practice; (2) who wish support these efforts....
Abstract Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six SCD at pre- and post-GT time points map somatic mutation clonal landscape gene-modified unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal burdens...