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Cell Reports Jul 2023Spermatogonial stem cells (SSCs) in the testis support the lifelong production of sperm. SSCs reside within specialized microenvironments called "niches," which are...
Spermatogonial stem cells (SSCs) in the testis support the lifelong production of sperm. SSCs reside within specialized microenvironments called "niches," which are essential for SSC self-renewal and differentiation. However, our understanding of the molecular and cellular interactions between SSCs and niches remains incomplete. Here, we combine spatial transcriptomics, computational analyses, and functional assays to systematically dissect the molecular, cellular, and spatial composition of SSC niches. This allows us to spatially map the ligand-receptor (LR) interaction landscape in both mouse and human testes. Our data demonstrate that pleiotrophin regulates mouse SSC functions through syndecan receptors. We also identify ephrin-A1 as a potential niche factor that influences human SSC functions. Furthermore, we show that the spatial re-distribution of inflammation-related LR interactions underlies diabetes-induced testicular injury. Together, our study demonstrates a systems approach to dissect the complex organization of the stem cell microenvironment in health and disease.
Topics: Male; Humans; Mice; Animals; Testis; Stem Cell Niche; Transcriptome; Semen; Spermatogonia; Cell Differentiation; Spermatogenesis
PubMed: 37393620
DOI: 10.1016/j.celrep.2023.112737 -
Nature Methods Oct 2023Single-cell proteomics by mass spectrometry is emerging as a powerful and unbiased method for the characterization of biological heterogeneity. So far, it has been...
Single-cell proteomics by mass spectrometry is emerging as a powerful and unbiased method for the characterization of biological heterogeneity. So far, it has been limited to cultured cells, whereas an expansion of the method to complex tissues would greatly enhance biological insights. Here we describe single-cell Deep Visual Proteomics (scDVP), a technology that integrates high-content imaging, laser microdissection and multiplexed mass spectrometry. scDVP resolves the context-dependent, spatial proteome of murine hepatocytes at a current depth of 1,700 proteins from a cell slice. Half of the proteome was differentially regulated in a spatial manner, with protein levels changing dramatically in proximity to the central vein. We applied machine learning to proteome classes and images, which subsequently inferred the spatial proteome from imaging data alone. scDVP is applicable to healthy and diseased tissues and complements other spatial proteomics and spatial omics technologies.
Topics: Animals; Mice; Proteome; Mass Spectrometry; Proteomics; Laser Capture Microdissection
PubMed: 37783884
DOI: 10.1038/s41592-023-02007-6 -
International Journal of Environmental... Aug 2023Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and... (Review)
Review
Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys-Dietz, and vascular Ehlers-Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs.
Topics: Humans; Ehlers-Danlos Syndrome, Type IV; Marfan Syndrome; Quality of Life; Aortic Diseases; Aorta
PubMed: 37623198
DOI: 10.3390/ijerph20166615 -
Nature Aug 2023Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development....
Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.
Topics: Adolescent; Adult; Female; Humans; Young Adult; Breast Neoplasms; Cell Lineage; Clone Cells; Epigenesis, Genetic; Epithelial Cells; Epithelium; Evolution, Molecular; Microdissection; Mutagenesis; Mutation; Mutation Rate; Premenopause; Tumor Microenvironment
PubMed: 37495687
DOI: 10.1038/s41586-023-06333-9 -
Nature Communications Nov 2023Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity...
Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer's Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer's dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD.
Topics: Humans; Aged; Genome-Wide Association Study; Meninges; Alzheimer Disease; Macrophages; Aging; Microglia
PubMed: 37923721
DOI: 10.1038/s41467-023-42825-y