Product Citations: 50

Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset.

In Nature Communications on 18 May 2025 by Golden, G. J., Wu, V. H., et al.

Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. However, characterization of the immunological processes occurring in human pancreatic lymphatic tissues is lacking. Here, we conduct a comprehensive study of immune cells from pancreatic, mesenteric, and splenic lymphatic tissues of non-diabetic control (ND), β cell autoantibody-positive non-diabetic (AAb+), and T1D donors using flow cytometry and CITEseq. Compared to ND pancreas-draining lymph nodes (pLN), AAb+ and T1D donor pLNs display decreased CD4+ Treg and increased stem-like CD8+ T cell signatures, while only T1D donor pLNs exhibit naive T cell and NK cell differentiation. Mesenteric LNs have modulations only in CD4+ Tregs and naive cells, while splenocytes lack these perturbations. Further, T cell expression of activation markers and IL7 receptor correlate with T1D genetic risk. These results demonstrate tissue-restricted immune changes occur before and after T1D onset.
© 2025. The Author(s).

  • FC/FACS
  • Homo sapiens (Human)
  • Immunology and Microbiology

Systematic discovery of single-cell protein networks in cancer with Shusi

Preprint on BioRxiv : the Preprint Server for Biology on 28 April 2025 by Zhang, T., Yu, J., et al.

Context-specific protein-protein interaction (PPI) drive heterogeneity of primary tumor, forming a formidable challenge to effective cancer therapy. However, systematically mapping and modeling these interactions at single-cell resolution across diverse cancer types remains an unmet need. Here, we present Shusi, a large language model-enhanced variational graph auto-encoder model trained on over 75,010 single-cell PPI networks across 23 cancer types, to predict context-specific PPIs. Shusi outperforms existing state-of-the-art methods, as validated through orthogonal experimental evidence. Cancer-specific mutations are significantly enriched in Shusi-predicted networks, offering complementary insights to conventional marker gene-based approaches. Through systematic evaluations, we demonstrate strong associations between Shusi-predicted network topologies, genetic vulnerabilities, and therapeutic sensitivity. Finally, in acute myeloid leukemia (AML), a blood cancer where cell-state heterogeneity drives clinical resistance, Shusi pinpointed JAK2 and SHP1 as actionable vulnerabilities of resistant leukemia subpopulations, as validated experimentally in primary AML. Shusi offers a deep-learning tool for implementing precision medicine based on single-cell protein network architecture.

  • Cancer Research

Human mitochondrial transfer modeling reveals biased delivery from mesenchymal-to-hematopoietic stem cells

Preprint on BioRxiv : the Preprint Server for Biology on 6 January 2025 by Dupard, S. J., Pinheiro, J. M., et al.

Within the bone marrow (BM), the intercellular communication between hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem/stromal cells (MSCs) is critical for the life-long maintenance of functional hematopoiesis. In recent years, the transfer of mitochondria between MSCs and HSPCs has emerged as a key aspect of this communication, occurring both in stress and homeostatic conditions. In human, the mesenchymal-to-hematopoietic transfer process and functional impact remain cryptic, primarily due to a lack of robust models. To this end, we here describe the development and exploitation of iMSOD-mito, an immortalized human MSCs line bearing an inducible mCherry mitochondrial tag. Co-culture with primary healthy HSPCs or a leukemic cell line revealed a high mitochondrial transfer rate (>15%), exclusively relying on cell-to-cell contact. While all CD34+ blood cells received mitochondria, a preferential transfer towards phenotypic hematopoietic stem cells was identified. Similarly, using primary MSCs with genetically labelled mitochondria we confirmed a transfer to all CD34+ populations, albeit occurring at a lower frequency than with the iMSOD-mito (3.38%). By engineering 3D bone marrow niches in perfusion bioreactor, this transfer rate could be significantly increased, while the biased towards HSC as receiver was maintained. Functionally, mitochondria-receiving cells exhibited an increased mitochondria membrane potential and reactive oxygen species (ROS) production, which in HSPCs was associated with retained quiescence in single cell divisional assay. In summary, we propose the iMSOD-mito as a standardized tool to model human mesenchymal-to-hematopoietic mitochondria transfer in 2D or 3D culture systems. Our work prompts the study of mitochondria transfer in both healthy or disease conditions, towards the design of regenerative therapies or identification of new targets in a malignant context.

  • Cell Biology
  • Stem Cells and Developmental Biology

Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.
© 2024. The Author(s).

  • Cancer Research
  • Genetics

Cellular crosstalk in the tumor microenvironment (TME) is still largely uncharacterized, while it plays an essential role in shaping immunosuppression or anti-tumor response. Large-scale analyses are needed to better decipher cell-cell communication in cancer. In this work, we used original and publicly available single-cell RNA sequencing (scRNAseq) data to characterize in-depth the communication networks in human clear cell renal cell carcinoma (ccRCC). We identified 50 putative communication channels specifically used by cancer cells to interact with other cells, including two novel angiogenin-mediated interactions. Expression of angiogenin and its receptors was validated at the protein level in primary ccRCC. Mechanistically, angiogenin enhanced ccRCC cell line proliferation and down-regulated secretion of IL-6, IL-8, and MCP-1 proinflammatory molecules. This study provides novel biological insights into molecular mechanisms of ccRCC, and suggests angiogenin and its receptors as potential therapeutic targets in clear cell renal cancer.
© 2023 The Author(s).

  • FC/FACS
  • Homo sapiens (Human)
  • Cancer Research
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