Biology subjects

SUN, W.

Publications and source records attributed to SUN, W..

3 recordsLinked to original sources

bioRxiv2025

Clonal memory of cell division in humans diverges between healthy haematopoiesis and acute myeloid leukaemia

Clonal memory, a cellular property inherited across at least two divisions, has emerged as a key driver of cell heterogeneity. To uncover its roles in human haematopoiesis, we developed high-resolution ex vivo tools that track both division and fate commitment of individual primary human haematopoietic stem and progenitor cells (HSPCs). We show that human HSPCs display a clonal memory of division, as cells descending from the same ancestor cell divide synchronously over multiple generations. In parallel, HSPCs inherit a clonal memory of fate commitment, independently of lineage identity. Both forms of clonal memory persist over at least two divisions, across different HSPC commitment stages and cell culture conditions. In contrast, malignant haematopoiesis exhibits lower synchronicity, revealing a disruption of clonal memory in leukemic cells. Epigenetic remodelling using a bromodomain inhibitor partially restores the clonal memory in division in leukemic HSPCs, highlighting the plasticity of this trait and its potential for therapeutic modulation. Our findings position clonal memory as a key regulator of human haematopoietic stem cell behaviour. Demonstrating that clonal memory can be modulated opens new avenues for tuning cell heterogeneity in healthy and pathological tissues.

cell biology↗

bioRxiv2024

scMitoMut for calling mitochondrial lineage related mutations in single cells

Tracing cell lineages has become a valuable tool for studying biological processes. Among the available tools for human data, mitochondria DNA (mtDNA) has a high potential due to its ability to be used in conjunction with single-cell chromatin accessibility data, giving access to the cell phenotype. Nonetheless, the existing mutation calling tools are ill-equipped to deal with the polyploid nature of the mtDNA and lack a robust statistical framework. Here we introduce scMitoMut, an innovative R package that leverages statistical methodologies to accurately identify mitochondrial lineage related mutations at the single-cell level. scMitoMut assigns a mutation quality q-value based on beta-binomial distribution to each mutation at each locus within individual cells, ensuring higher sensitivity and precision of lineage related mutation calling in comparison to current methodologies. We tested scMitoMut using single-cell DNA sequencing, scATAC sequencing and 10x Genomics single cell multiome datasets. Using a single-cell DNA sequencing dataset from a mixed population of cell lines, scMitoMut demonstrated superior sensitivity in identifying small proportion of cancer cell lines compared to existing methods. In a human colorectal cancer scATAC dataset, scMitoMut identified more mutations than state-of-the-art methods. Applied to 10x Genomics multiome datasets, scMitoMut effectively measured the lineage distance in cells from blood or brain tissues. Thus, the scMitoMut is a free available (https://www.bioconductor.org/packages/devel/bioc/html/scMitoMut.html.), well-engineered toolkit for mtDNA mutation calling with high memory and CPU efficiency. Consequently, it will significantly advance the application of single-cell sequencing, facilitating the precise delineation of mitochondrial mutations for lineage tracing purposes in development, tumor and stem cell biology.

bioinformatics↗

bioRxiv2024

Humanized in vivo bone marrow models orchestrate multi-lineage human hematopoietic cell development

Hematopoiesis develops in the bone marrow (BM) where multiple interactions regulate differentiation and preservation of hematopoietic stem/progenitor cells (HSPCs). Although murine BM has been extensively analyzed, the human BM microenvironment remains less understood. Immune-deficient murine models have enabled the analysis of molecular and cellular regulation of human HSPCs, which remains limited as human hematopoietic cells develop in xenogenic microenvironments. In this study, we thoroughly characterized a humanized (h) in vivo BM model, based on mesenchymal stromal cell (MSC) differentiation (called hOssicles (hOss)), and hematopoietic cell compartments generated 3 months post-transplant of CD34+ cells using single-cell RNA sequencing and cellular barcoding. Serial isolation of MSCs and HSPCs from hOss and transplant experiments revealed the dynamic nature of these hBM niches. hOss altered human hematopoietic development by modulating myeloid/lymphoid cell production and HSPC levels. Clonal tracking highlighted hematopoietic cell cross-talks between the murine BM and hOss, indicating the multipotent or more restricted lineage origin of human hematopoiesis shared in the BM sites.

cell biology↗