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Lifelong tissue memory relies on spatially organized dedicated progenitors located distally from the injury [scRNAseq_gradient]

ABSTRACT: It is believed epithelial cells that have participated in a wound repair elicit a more efficient but locally restricted response to future injuries. However here we show that the cell adaptation resulting from a localised tissue damage has a wide spatial impact at a scale not previously noticed. We demonstrate that away from injured site, after a first injury a specific epithelial stem cell population gives rise to long term wound-memory progenitors residing in their own niche of origin. Notably these progenitors have not taken part in the first wound healing but become pre-activated through priming. This adaptation differs from classical features of trained immunity previously shown to be adopted by other epithelial stem cells. Our newly identified wound-distal memory cells display an intrinsic pre-activated state, maintained at chromatin and transcriptional level, leading to an enhanced wound repair ability that can be partially recapitulated through epigenetic perturbation even in absence of an injury. Importantly, the harmful consequences of wound repair, such as exacerbated tumorigenesis, occur within these primed cells and follow their spatial distribution. Overall, we show that sub-organ scale adaptation of an injury relies on spatially organized and memory-dedicated progenitors, characterized by a chromatin actionable cell state, that establishes an epigenetic field cancerization and predisposes to tumour onset.

ORGANISM(S): Mus musculus

PROVIDER: GSE221405 | GEO | 2023/02/02

REPOSITORIES: GEO

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Lifelong tissue memory relies on spatially organized dedicated progenitors located distally from the injury [bulkRNAseq]

Project description:It is believed epithelial cells that have participated in a wound repair elicit a more efficient but locally restricted response to future injuries. However here we show that the cell adaptation resulting from a localised tissue damage has a wide spatial impact at a scale not previously noticed. We demonstrate that away from injured site, after a first injury a specific epithelial stem cell population gives rise to long term wound-memory progenitors residing in their own niche of origin. Notably these progenitors have not taken part in the first wound healing but become pre-activated through priming. This adaptation differs from classical features of trained immunity previously shown to be adopted by other epithelial stem cells. Our newly identified wound-distal memory cells display an intrinsic pre-activated state, maintained at chromatin and transcriptional level, leading to an enhanced wound repair ability that can be partially recapitulated through epigenetic perturbation even in absence of an injury. Importantly, the harmful consequences of wound repair, such as exacerbated tumorigenesis, occur within these primed cells and follow their spatial distribution. Overall, we show that sub-organ scale adaptation of an injury relies on spatially organized and memory-dedicated progenitors, characterized by a chromatin actionable cell state, that establishes an epigenetic field cancerization and predisposes to tumour onset.

2023-02-02 | GSE221403 | GEO

Lifelong tissue memory relies on spatially organized dedicated progenitors located distally from the injury [ATAC-Seq]

2023-02-02 | GSE221408 | GEO

Transcriptional analysis of injured airway epithelial cells in Mmp7-null and wildtype mice

Project description:Matrix metalloproteinase 7 (MMP7) is expressed at low levels in intact, normal airways by non-mucous-producing cells, including ciliated cells. In response to injury and infection, MMP7 expression is quickly and markedly upregulated and functions to regulate wound repair and various mucosal immune processes. We evaluated the global transcriptional response of airway epithelial cells from wild type and Mmp7-null mice cultured at an air-liquid interface. A common injury response was seen in both genotypes with up-regulation of genes associated with proliferation and migration. Analysis of differentially expressed genes between genotypes after injury revealed enrichment of functional categories associated with inflammation, cilia and differentiation. Because these analyses suggested MMP7 regulated ciliogenesis, we evaluated the recovery of the airway epithelium in wild type and Mmp7-null mice in vivo after naphthalene injury. These studies identified a new role for MMP7 in attenuating ciliogenesis during wound repair. A total of 16 air-liquid interface cultures of mouse airway epithelial cells were studied under four conditions: 1. Mmp7-null, no injury (n = 4); 2. Mmp7-null, scratch injury (n = 4); 3. Wildtype, no injury (n =4); 4. Wiltype, scratch injury (n = 4).

2012-11-01 | E-GEOD-38513 | biostudies-arrayexpress

Defining stem cell dynamics and migration during wound healing in mouse skin epidermis (D4 post-wound)

Project description:Wound healing is essential to repair the skin after injury. In the epidermis, distinct stem cells (SCs) populations contribute to wound healing. However, how SCs balance proliferation, differentiation and migration to repair a wound remains poorly understood. Here we show the cellular and molecular mechanisms that regulate wound healing in mouse tail epidermis. Using a combination of proliferation kinetics experiments and molecular profiling, we identify the gene signatures associated with proliferation, differentiation and migration in different regions surrounding the wound. Functional experiments show that SC proliferation, migration and differentiation can be uncoupled during wound healing. Lineage tracing and quantitative clonal analysis reveal that, following wounding, progenitors divide more rapidly, but conserve their homeostatic mode of division, leading to their rapid depletion whereas SCs become active, giving rise to new progenitors that expand and repair the wound. These results have important implications for tissue regeneration, acute and chronic wound disorders.

2017-02-28 | GSE93638 | GEO

Defining stem cell dynamics and migration during wound healing in mouse skin epidermis

2017-02-28 | GSE76795 | GEO

Integrated spatial multi-omics reveals fibroblast fate during tissue repair

Project description:In the skin, tissue injury results in fibrosis in the form of scars composed of dense extracellular matrix deposited by fibroblasts. The therapeutic goal of regenerative wound healing has remained elusive in part because principles of fibroblast programming and adaptive response to injury remain incompletely understood. Here, we present a multimodal -omics platform for the comprehensive study of cell populations in complex tissue, which has allowed us to characterize the cells involved in wound healing across both time and space. We employ a stented wound model that recapitulates human tissue repair kinetics and multiple Rainbow transgenic lines to precisely track fibroblast fate during the physiologic response to injury. Through integrated analysis of single cell chromatin landscapes and gene expression states, coupled with spatial transcriptomic profiling, we are able to impute fibroblast epigenomes with temporospatial resolution. This has allowed us to define the mechanisms controlling cell fate during migration, proliferation, and differentiation following tissue injury and thereby reexamine the canonical phases of wound healing. We show that wounding triggers a polyclonal proliferation of tissue-resident, mechano-responsive fibroblasts, the subpopulations of which inhabit spatially-distinct regions within the wound and harbor distinct activities. These findings have broad implications for the study of tissue repair in complex organ systems.

2021-06-24 | GSE178758 | GEO

An atlas of healthy and injured cell states and niches in the human kidney [scRNA-Seq]

Project description:Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, and interactions within tissue neighborhoods. We applied multiple single-cell or -nucleus assays (>400,000 nuclei/cells) and spatial imaging technologies to a broad spectrum of healthy reference (45 donors) and diseased (48 patients) kidneys. This has provided a high resolution cellular atlas of 51 main cell types that include rare and novel cell populations. The multi-omic approach provides detailed transcriptomic profiles, epigenomic regulatory factors, and spatial localizations spanning the entire kidney. We further define 28 cellular states across nephron segments and interstitium that were altered in kidney injury, encompassing cycling, adaptive or maladaptive repair, transitioning and degenerative states. Molecular signatures permitted localization of these states within injury neighborhoods using spatial transcriptomics, while large-scale 3D imaging analysis (~1.2 million neighborhoods) provided corresponding linkages to active immune responses. These analyses defined biological pathways relevant to injury time-course and niches, including signatures underlying epithelial repair that predicted maladaptive states associated with a decline in kidney function. This integrated multimodal spatial cell atlas of healthy and diseased human kidneys represents the most comprehensive benchmark of cellular states, neighborhoods, outcome-associated signatures, and publicly available interactive visualizations.

2022-10-10 | GSE199711 | GEO

An atlas of healthy and injured cell states and niches in the human kidney [snCv3]

2022-10-10 | GSE183277 | GEO

An atlas of healthy and injured cell states and niches in the human kidney [Slide-seq2]

2022-10-10 | GSE183274 | GEO

An atlas of healthy and injured cell states and niches in the human kidney [SNARE-Seq2]

2022-10-10 | GSE183273 | GEO