The developmental pathways that lead to the production of antigen-presenting dendritic cells (DCs) are beginning to be understood. These are the last of the pathways of haematopoiesis to be mapped. ...The existence of many specialized subtypes of DC has complicated this endeavour, as has the need to distinguish the DCs formed in steady state from those produced during an inflammatory response. Here we review studies that lead to the concept that different types of DC develop through different branches of haematopoietic pathways that involve different immediate precursor cells. Furthermore, these studies show that many individual tissues generate their own DCs locally, from a reservoir of immediate DC precursors, rather than depending on a continuous flux of DCs from the bone marrow.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Understanding intratumoral heterogeneity--the molecular variation among cells within a tumor--promises to address outstanding questions in cancer biology and improve the diagnosis and treatment of ...specific cancer subtypes. Single-cell analyses, especially RNA sequencing and other genomics modalities, have been transformative in revealing novel biomarkers and molecular regulators associated with tumor growth, metastasis and drug resistance. However, these approaches fail to provide a complete picture of tumor biology, as information on cellular location within the tumor microenvironment is lost. New technologies leveraging multiplexed fluorescence, DNA, RNA and isotope labeling enable the detection of tens to thousands of cancer subclones or molecular biomarkers within their native spatial context. The expeditious growth in these techniques, along with methods for multiomics data integration, promises to yield a more comprehensive understanding of cell-to-cell variation within and between individual tumors. Here we provide the current state and future perspectives on the spatial technologies expected to drive the next generation of research and diagnostic and therapeutic strategies for cancer. This Review describes spatial omics and multiplexed imaging technologies and their current and future impact in studying tumor heterogeneity and cancer biology.
The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, ...considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
•Evidence that supports that DCs are a separate lineage to myeloid and lymphoid.•Summary of DC development at a clonal level.•Description of single cell lineage tracing technologies and their ...findings.•Placement of DC development within the emerging continuous model of haematopoiesis.•Reconciliation of controversies surrounding DC development.
Understanding development of the dendritic cell (DC) subtypes continues to evolve. The origin and relationship of conventional DC type 1 (cDC1), cDC type 2 (cDC2) and plasmacytoid DCs (pDCs) to each other, and in relation to classic myeloid and lymphoid cells, has had a long and controversial history and is still not fully resolved. This review summarises the technological developments and findings that have been achieved at a clonal level, and how that has enhanced our knowledge of the process. It summarises the single cell lineage tracing technologies that have emerged, their application in in vitro and in vivo studies, in both mouse and human settings, and places the findings in a wider context of understanding haematopoiesis at a single cell or clonal level. In particular, it addresses the fate heterogeneity observed in many phenotypically defined progenitor subsets and how these findings have led to a departure from the classic ball-and-stick models of haematopoiesis to the emerging continuous model. Prior contradictions in DC development may be reconciled if they are framed within this revised model, where commitment to a lineage or cell type does not occur in an all-or-nothing process in defined progenitors but rather can occur at many stages of haematopoiesis in a dynamic process.
Single-cell RNA sequencing (scRNA-seq) technology allows researchers to profile the transcriptomes of thousands of cells simultaneously. Protocols that incorporate both designed and random barcodes ...have greatly increased the throughput of scRNA-seq, but give rise to a more complex data structure. There is a need for new tools that can handle the various barcoding strategies used by different protocols and exploit this information for quality assessment at the sample-level and provide effective visualization of these results in preparation for higher-level analyses. To this end, we developed scPipe, an R/Bioconductor package that integrates barcode demultiplexing, read alignment, UMI-aware gene-level quantification and quality control of raw sequencing data generated by multiple protocols that include CEL-seq, MARS-seq, Chromium 10X, Drop-seq and Smart-seq. scPipe produces a count matrix that is essential for downstream analysis along with an HTML report that summarises data quality. These results can be used as input for downstream analyses including normalization, visualization and statistical testing. scPipe performs this processing in a few simple R commands, promoting reproducible analysis of single-cell data that is compatible with the emerging suite of open-source scRNA-seq analysis tools available in R/Bioconductor and beyond. The scPipe R package is available for download from https://www.bioconductor.org/packages/scPipe.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relationship between dendritic cells (DCs) and macrophages is often debated. Here we ask whether steady-state, lymphoid-tissue-resident conventional DCs (cDCs), plasmacytoid DCs (pDCs), and ...macrophages share a common macrophage-DC-restricted precursor (MDP). Using new clonal culture assays combined with adoptive transfer, we found that MDP fractions isolated by previous strategies are dominated by precursors of macrophages and monocytes, include some multipotent precursors of other hematopoietic lineages, but contain few precursors of resident cDCs and pDCs and no detectable common precursors restricted to these DC types and macrophages. Overall we find no evidence for a common restricted MDP leading to both macrophages and FL-dependent, resident cDCs and pDCs.
•A common “macrophage-DC progenitor” (MDP) is not an intermediate in DC development•MDPs contain precursors for other lineages•The cytokine FL is important in both the early and late stages of DC development
A common progenitor of macrophages and steady-state dendritic cells has been postulated by the description of a progenitor restricted to these cell types. Using novel assays, Sathe et al. report no evidence of such a common, restricted progenitor.
Antigen presentation is typically regarded as the domain of immune cells such as dendritic cells and B cells. Hernandez-Malmierca et al. (2022) upend this notion by observing that hematopoietic stem ...and progenitor cells process and present antigen via major histocompatibility class II as a means of CD4+ T cell-mediated immune surveillance.
Antigen presentation is typically regarded as the domain of immune cells such as dendritic cells and B cells. Hernandez-Malmierca et al. (2022) upend this notion by observing that hematopoietic stem and progenitor cells process and present antigen via major histocompatibility class II as a means of CD4+ T cell-mediated immune surveillance.
Haematopoietic stem cells (HSCs) and their subsequent progenitors produce blood cells, but the precise nature and kinetics of this production is a contentious issue. In one model, lymphoid and ...myeloid production branch after the lymphoid-primed multipotent progenitor (LMPP), with both branches subsequently producing dendritic cells. However, this model is based mainly on in vitro clonal assays and population-based tracking in vivo, which could miss in vivo single-cell complexity. Here we avoid these issues by using a new quantitative version of 'cellular barcoding' to trace the in vivo fate of hundreds of LMPPs and HSCs at the single-cell level. These data demonstrate that LMPPs are highly heterogeneous in the cell types that they produce, separating into combinations of lymphoid-, myeloid- and dendritic-cell-biased producers. Conversely, although we observe a known lineage bias of some HSCs, most cellular output is derived from a small number of HSCs that each generates all cell types. Crucially, in vivo analysis of the output of sibling cells derived from single LMPPs shows that they often share a similar fate, suggesting that the fate of these progenitors was imprinted. Furthermore, as this imprinting is also observed for dendritic-cell-biased LMPPs, dendritic cells may be considered a distinct lineage on the basis of separate ancestry. These data suggest a 'graded commitment' model of haematopoiesis, in which heritable and diverse lineage imprinting occurs earlier than previously thought.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Innate lymphoid cells (ILCs) are enriched at mucosal surfaces, where they provide immune surveillance. All ILC subsets develop from a common progenitor that gives rise to pre-committed progenitors ...for each of the ILC lineages. Currently, the temporal control of gene expression that guides the emergence of these progenitors is poorly understood. We used global transcriptional mapping to analyze gene expression in different ILC progenitors. We identified PD-1 to be specifically expressed in PLZF+ ILCp and revealed that the timing and order of expression of the transcription factors NFIL3, ID2, and TCF-1 was critical. Importantly, induction of ILC lineage commitment required only transient expression of NFIL3 prior to ID2 and TCF-1 expression. These findings highlight the importance of the temporal program that permits commitment of progenitors to the ILC lineage, and they expand our understanding of the core transcriptional program by identifying potential regulators of ILC development.
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•ILCp transcriptomics define the blueprint for hierarchical ILC development•PD-1 identifies the PLZF-expressing ILC precursor in the bone marrow•Transient NFIL3 expression prior to ID2 expression is required for ILC development•ID2 and TCF-1 are required to extinguish stem cell and B and T cell gene programs
Seillet et al. define the hierarchical blueprint for ILC development using global transcriptomic analyses of ILC progenitors. This revealed that PD-1 is a key marker of ILCp and uncovered a regulatory circuit governed by NFIL3 in regulating ID2 and TCF-1 essential for ILC differentiation.
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