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1.
Cell ; 2024 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-39454574

RESUMO

Elucidating organismal developmental processes requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by reconstructions of cellular trajectories. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling in silico fate-mapping experiments. To demonstrate the versatility of our multimodal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of neuro-mesodermal progenitors (NMPs) and the origins of a joint kidney-hemangioblast progenitor population.

2.
Nature ; 603(7900): 309-314, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35236985

RESUMO

The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. We observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.


Assuntos
Parabiose , Análise de Célula Única , Adipócitos , Envelhecimento/genética , Transporte de Elétrons/genética , Células-Tronco Hematopoéticas , Hepatócitos , Células-Tronco Mesenquimais , Mitocôndrias , Especificidade de Órgãos/genética , RNA-Seq , Rejuvenescimento
4.
MethodsX ; 13: 102958, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39329153

RESUMO

Single-cell sequencing has revolutionized our understanding of cellular heterogeneity and cell state, enabling investigations across diverse fields such as developmental biology, immunology, and cancer biology. However, obtaining a high-quality single-cell suspension is still challenging, particularly when starting with limited materials like Zebrafish embryos, a powerful animal model for studying developmental processes and human diseases. Here, we present an optimized protocol for isolating single cells from individual zebrafish embryos, offering a valuable resource for researchers interested in working with limited starting material. The protocol facilitates unique investigations utilizing individual embryos, such as inter-individual genetic differences and embryo-specific lineage tracing analysis. Using a refined single-cell isolation protocol alongside zebrafish as a model organism, researchers can access a resource for exploring the emergence of all types and states of cells, advancing our understanding of cellular processes and disease mechanisms.

5.
bioRxiv ; 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38712150

RESUMO

Mycobacterium tuberculosis (MTB) infects and replicates in lung mononuclear phagocytes (MNPs) with astounding ability to evade elimination. ESX-1, a type VII secretion system, acts as a virulence determinant that contributes to MTB's ability to survive within MNPs, but its effect on MNP recruitment and/or differentiation remains unknown. Here, using single-cell RNA sequencing, we studied the role of ESX-1 in MNP heterogeneity and response in mice and murine bone marrow-derived macrophages (BMDM). We found that ESX-1 is required for MTB to recruit diverse MNP subsets with high MTB burden. Further, MTB induces an anti-inflammatory signature in MNPs and BMDM in an ESX-1 dependent manner. Similarly, spatial transcriptomics revealed an upregulation of anti-inflammatory signals in MTB lesions, where monocyte-derived macrophages concentrate near MTB-infected cells. Together, our findings suggest that MTB ESX-1 mediates the recruitment and differentiation of anti-inflammatory MNPs, which MTB can infect and manipulate for survival.

6.
J Clin Invest ; 134(17)2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-39225101

RESUMO

Metastasis is the leading cause of cancer-related deaths. It is unclear how intratumor heterogeneity (ITH) contributes to metastasis and how metastatic cells adapt to distant tissue environments. The study of these adaptations is challenged by the limited access to patient material and a lack of experimental models that appropriately recapitulate ITH. To investigate metastatic cell adaptations and the contribution of ITH to metastasis, we analyzed single-cell transcriptomes of matched primary tumors and metastases from patient-derived xenograft models of breast cancer. We found profound transcriptional differences between the primary tumor and metastatic cells. Primary tumors upregulated several metabolic genes, whereas motility pathway genes were upregulated in micrometastases, and stress response signaling was upregulated during progression. Additionally, we identified primary tumor gene signatures that were associated with increased metastatic potential and correlated with patient outcomes. Immune-regulatory control pathways were enriched in poorly metastatic primary tumors, whereas genes involved in epithelial-mesenchymal transition were upregulated in highly metastatic tumors. We found that ITH was dominated by epithelial-mesenchymal plasticity (EMP), which presented as a dynamic continuum with intermediate EMP cell states characterized by specific genes such as CRYAB and S100A2. Elevated expression of an intermediate EMP signature correlated with worse patient outcomes. Our findings identified inhibition of the intermediate EMP cell state as a potential therapeutic target to block metastasis.


Assuntos
Neoplasias da Mama , Transição Epitelial-Mesenquimal , Metástase Neoplásica , Análise de Célula Única , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Animais , Camundongos , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem Celular Tumoral
7.
Life Sci Alliance ; 6(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36526371

RESUMO

Spatial transcriptomics extends single-cell RNA sequencing (scRNA-seq) by providing spatial context for cell type identification and analysis. Imaging-based spatial technologies such as multiplexed error-robust fluorescence in situ hybridization (MERFISH) can achieve single-cell resolution, directly mapping single-cell identities to spatial positions. MERFISH produces a different data type than scRNA-seq, and a technical comparison between the two modalities is necessary to ascertain how to best integrate them. We performed MERFISH on the mouse liver and kidney and compared the resulting bulk and single-cell RNA statistics with those from the Tabula Muris Senis cell atlas and from two Visium datasets. MERFISH quantitatively reproduced the bulk RNA-seq and scRNA-seq results with improvements in overall dropout rates and sensitivity. Finally, we found that MERFISH independently resolved distinct cell types and spatial structure in both the liver and kidney. Computational integration with the Tabula Muris Senis atlas did not enhance these results. We conclude that MERFISH provides a quantitatively comparable method for single-cell gene expression and can identify cell types without the need for computational integration with scRNA-seq atlases.


Assuntos
Análise de Célula Única , Transcriptoma , Camundongos , Animais , Hibridização in Situ Fluorescente/métodos , Análise de Célula Única/métodos , Transcriptoma/genética , Perfilação da Expressão Gênica/métodos , RNA-Seq
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