Single-Cell Map of Dynamic Multicellular Ecosystem of Radiation-Induced Intestinal Injury
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165318 | GEO | 2023/03/06
REPOSITORIES: GEO
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Project description:Single-Cell Map of Dynamic Multicellular Ecosystem of Radiation-Induced Intestinal Injury
| PRJNA694067 | ENA
Project description:Intestinal epithelial stem cells (ISCs) are the focus of recent intense study. Current in vitro models rely on supplementation with the Wnt agonist R-spondin1 to support robust growth, ISC self-renewal, and differentiation. Intestinal subepithelial myofibroblasts (ISEMFs) are important supportive cells within the ISC niche. We hypothesized that co-culture with ISEMF enhances the growth of ISCs in vitro and allows for their successful in vivo implantation and engraftment. ISC-containing small intestinal crypts, FACS-sorted single ISCs, and ISEMFs were procured from C57BL/6 mice. Crypts and single ISCs were grown in vitro into enteroids, in the presence or absence of ISEMFs. ISEMFs enhanced the growth of intestinal epithelium in vitro in a proximity-dependent fashion, with co-cultures giving rise to larger enteroids than monocultures. Co-culture of ISCs with supportive ISEMFs relinquished the requirement of exogenous R-spondin1 to sustain long-term growth and differentiation of ISCs. Mono- and co-cultures were implanted subcutaneously in syngeneic mice. Co-culture with ISEMFs proved necessary for successful in vivo engraftment and proliferation of enteroids; implants without ISEMFs did not survive. ISEMF whole transcriptome sequencing and qPCR demonstrated high expression of specific R-spondins, well-described Wnt agonists that supports ISC growth. Specific non-supportive ISEMF populations had reduced expression of R-spondins. The addition of ISEMFs in intestinal epithelial culture therefore recapitulates a critical element of the intestinal stem cell niche and allows for its experimental interrogation and biodesign-driven manipulation. Two samples of intestinal subepithelial myofibroblasts were used in this study.
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Project description:Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment and tumor development. Here, we generated > 70,000 single-cell transcriptomes for 10 HCC patients from four relevant sites: primary tumor, portal vein tumor thrombus (PVTT), metastatic lymph node and non-tumor liver. We discovered a cluster of antitumor central memory T cells enriched in intratumoral tertiary lymphoid structures (TLSs) of HCC. We found chronic HBV/HCV infection increases the infiltration of CD8+ T cells in tumors but aggravates the exhaustion of tumor-infiltrating lymphocytes. We identified MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and two distinct differentiation trajectories are related to their accumulation. We further demonstrated MMP9+ TAMs can promote HCC cells migration, invasion and angiogenesis. Our data also revealed the heterogeneous population of malignant hepatocytes and found they might play multifaceted roles in shaping the immune microenvironment of HCC. Finally, we identified seven TME subtypes of HCC that can predict patient prognosis. Collectively, this large-scale, single-cell atlas deepens our understanding of the ecosystem in primary and metastatic HCCs, might facilitating identification of new immune therapy strategies for this malignancy.
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Project description:Perturbed intestinal epithelial homeostasis demonstrated as decreased Lgr5+ intestinal stem cells (Lgr5 ISCs) and increased secretory lineages were observed in our study where Lkb1 was specfically deleted in Lgr5 ISCs using Lgr5-EGFP-creERT2 (Tamoxifen) deletor. To gain mechanistic insight how Lkb1 maintains intestinal epithelial stem cell homeostasis, Lkb1 deficient ISCs (Lgr5-high cells) and progenitors (Lgr5-low cells) are isolated by flow cytometry and profiled by RNA sequencing to compare with controls (Lkb1 wild type ISCs and progenitors).
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Project description:Microvascular invasion (MVI) is a significant pathological feature of hepatocellular carcinoma (HCC) associated with poor outcomes, early recurrence, and intrahepatic metastasis in post-surgical resection and transplant patients. However, the tumor microenvironment (TME) and transcriptional programs underlying MVI remain poorly understood. In this study, we conducted single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) HCC patients, providing a comprehensive single-cell atlas of MVI. Single-cell dissection of the multicellular ecosystem revealed the emergence or expansion of cycling T cells, LAMP3+ dendritic cells, TREM2+ macrophages, myofibroblasts, and tumor-promoting arterial i endothelial cells within the MVI+ TME. MVI+ malignant cells are characterized by high proliferation rates and the ability to evade immune detection through the upregulation of non-classical MHC class I molecules. In contrast, MVI-malignant cells exhibit an inflammatory milieu. Furthermore, we identified the CCL16/CCR1 interaction between TREM2+ macrophages and malignant cells as a contributing factor in MVI formation and tumor progression. Notably, we identified a unique multicellular module that plays the dominant role in shaping the immunosuppressive microenvironment of MVI and correlates with poor prognosis. In summary, these findings enhance our understanding of the underlying cellular and molecular mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.
2023-09-12 | GSE242889 | GEO
Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GHD). We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures demonstrating the persistence of the maladaptive impact of an in vivo inflammatory encounter by the ISCs. Thus, inflammation from GI GVHD leaves a memory of its effects on ISCs that persist and are likely to affect their sensitivity to adapt to future stress or challenges.
2024-09-11 | GSE243364 | GEO
Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. We performed transposase-accessible chromatin sequencing (ATAC-seq) in sorted Lgr5+ISCs harvested from the BALB/c→B6-GFP-Lgr5 model of GVHD.
2024-09-11 | GSE223814 | GEO
Project description:Intestinal epithelial stem cells (ISCs) are the focus of recent intense study. Current in vitro models rely on supplementation with the Wnt agonist R-spondin1 to support robust growth, ISC self-renewal, and differentiation. Intestinal subepithelial myofibroblasts (ISEMFs) are important supportive cells within the ISC niche. We hypothesized that co-culture with ISEMF enhances the growth of ISCs in vitro and allows for their successful in vivo implantation and engraftment. ISC-containing small intestinal crypts, FACS-sorted single ISCs, and ISEMFs were procured from C57BL/6 mice. Crypts and single ISCs were grown in vitro into enteroids, in the presence or absence of ISEMFs. ISEMFs enhanced the growth of intestinal epithelium in vitro in a proximity-dependent fashion, with co-cultures giving rise to larger enteroids than monocultures. Co-culture of ISCs with supportive ISEMFs relinquished the requirement of exogenous R-spondin1 to sustain long-term growth and differentiation of ISCs. Mono- and co-cultures were implanted subcutaneously in syngeneic mice. Co-culture with ISEMFs proved necessary for successful in vivo engraftment and proliferation of enteroids; implants without ISEMFs did not survive. ISEMF whole transcriptome sequencing and qPCR demonstrated high expression of specific R-spondins, well-described Wnt agonists that supports ISC growth. Specific non-supportive ISEMF populations had reduced expression of R-spondins. The addition of ISEMFs in intestinal epithelial culture therefore recapitulates a critical element of the intestinal stem cell niche and allows for its experimental interrogation and biodesign-driven manipulation.
2013-12-20 | GSE52402 | GEO
Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. Single cells were isolated from small intestine crypts from Allo (BALB/c→C57BL/6) or Syn (C57BL/6→C57BL/6) transplant 7 days after bone marrow transplantation (BMT) and analyzed using scRNA-seq.
2024-09-11 | GSE223368 | GEO
Project description:The intestine has a remarkable capacity to regenerate during homeostasis by the vigorous intestinal stem cells (ISCs) that reside in the base of the crypts. ISCs are easily impaired by DNA damage due to their active cell cycle. Intriguingly, certain cell populations possess the dedifferentiating ability to restore ISCs after ablation, although the molecular mechanisms by which these cells dedifferentiate into ISCs are largely unknown. Here, we performed single-cell RNA-seq using wild type and Phf16 knockout mice from normal or after irradiation to elucidate molecular mechanisms of Phf16 in intestinal regeneration. Our work characterizes that Phf16 is crucial for downregulating stemness in revival stem cells.
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