Single-cell transcriptomic and spatial landscapes of the developing human pancreas

Olaniru, Oladapo E.; Kadolsky, Ulrich D.; Kannambath, Shichina; Vaikkinen, Heli; Fung, Kathy; Dhami, Pawan; Persaud, Shanta J.

doi:10.1016/j.cmet.2022.11.009

Cited by 41 publications

(27 citation statements)

References 90 publications

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“…As a result, single cell studies of the human pancreas have included very few samples (75,76) or embryonic samples (77) and have focused on endocrine cells less susceptible to degradation. Previous autopsy studies on pancreata of patients deceased with no known pancreas pathology revealed frequent PanINs and KRAS mutations (10,(14)(15)(16)(17)(31)(32)(33)(34)(35)(36)78), but the samples mainly represented older individuals with limited transcriptional profiling performed.…”

Section: Discussionmentioning

confidence: 99%

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

Carpenter

Elhossiny

Kadiyala

et al. 2023

Preprint

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The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

Carpenter

Elhossiny

Kadiyala

et al. 2023

Preprint

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“…Scale bar: 20 μm. (c) Violin plot depicting the expression of endocrine progenitor‐enriched genes (pink) from scRNAseq data of human fetal pancreas 11 …”

Section: Human Pancreas Developmentmentioning

confidence: 99%

“…This allows for the identification of heterogeneity within a subpopulation of cells in a tissue and follow‐up studies antibodies can be directed against surface markers to help distinguish cell subtypes, as has been carried out for human beta cells 31 . The use of scRNAseq to measure changes in the transcriptome of the human fetal pancreas over a range of gestational stages has recently allowed data mining of potential genes related to beta cell development 11,13 . In addition, these studies have provided information on pseudo‐time ordering, which has led to improved understanding of the order in which genes are expressed during pancreatic cell lineage specification 11,13 .…”

Section: Single‐cell Rna Sequencingmentioning

confidence: 99%

“…Cell–cell interactions within the developing human pancreas. (a) Schematic showing the spatial proximity of the different cell types identified by spatial transcriptomics of the developing human pancreas 11 . (b) Circos plot showing predicted ligand‐receptor pairs from cell–cell connectivity analysis of human fetal pancreatic cells at 12–20 PCW 11 …”

Section: Pancreatic Microenvironmentmentioning

confidence: 99%

“…5,10 Recent studies using multi-omics technologies are beginning to shed light on the molecular landscapes of the human fetal pancreas at multiple developmental stages at a single-cell resolution. [11][12][13][14] The detailed information obtained from profiling pancreatic progenitor cells as they differentiate and mature into beta cells over different stages of development will be of critical assistance to the global effort of producing functional beta-like cells in vitro, which will not require additional maturation steps before clinical use. This review will provide an overview of recent developments in the multi-omics analysis of the developing human pancreas.…”

Section: Introductionmentioning

confidence: 99%

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Using single‐cell multi‐omics screening of human fetal pancreas to identify novel players in human beta cell development

2022

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Islet transplantation from organ donors can considerably improve glucose homeostasis and well‐being in individuals with type 1 diabetes, where the beta cells are destroyed by the autoimmune attack, but there are insufficient donor islets to make this a widespread therapy. Strategies are therefore being developed to generate unlimited amounts of insulin‐producing beta cells from pluripotent stem cells, with the aim that they will be transplanted to treat diabetes. Whilst much progress has been made in recent years in the directed differentiation of pluripotent stem cells to beta‐like cells, essential gaps still exist in generating stem cell‐derived beta cells that are fully functional in vitro. This short review provides details of recent multi‐‘omics’ studies of the human fetal pancreas, which are revealing granular information on the various cell types in the developing pancreas. It is anticipated that this fine mapping of the pancreatic cells at single‐cell resolution will provide additional insights that can be utilised to reproducibly produce human beta cells in vitro that have the functional characteristics of beta cells within native human islets.

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Single‐cell sequencing combined with spatial transcriptomics reveals that the IRF7 gene in M1 macrophages inhibits the occurrence of pancreatic cancer by regulating lipid metabolism‐related mechanisms

Zhan,

Zou,

Han

et al. 2024

Clinical & Translational Med

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AimThe main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1‐type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression.MethodsBy utilising single‐cell RNA sequencing (scRNA‐seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co‐culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage‐derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage‐derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage‐derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation‐associated proteins in tumour tissues was examined using immunohistochemistry.ResultsThrough combined analysis of scRNA‐seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macrophages can also suppress lipid metabolism, cell viability, proliferation, migration, invasion and intratumoural formation capacity of PAAD cells, while promoting cell apoptosis.ConclusionOverexpression of IRF7 in M1 macrophages may inhibit RPS18 transcription, reduce the transfer of RPS18 from M1 macrophage‐derived exosomes to PAAD cells, thereby suppressing ILF3 expression in PAAD cells, inhibiting the lipid metabolism pathway, and curtailing the viability, proliferation, migration, invasion of PAAD cells, as well as enhancing cell apoptosis, ultimately inhibiting tumour formation in PAAD cells in vivo. Targeting IRF7/RPS18 in M1 macrophages could represent a promising immunotherapeutic approach for PAAD in the future.

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Single-cell transcriptomic and spatial landscapes of the developing human pancreas

Cited by 41 publications

References 90 publications

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early pre-neoplastic pancreatic lesions

Using single‐cell multi‐omics screening of human fetal pancreas to identify novel players in human beta cell development

Single‐cell sequencing combined with spatial transcriptomics reveals that the IRF7 gene in M1 macrophages inhibits the occurrence of pancreatic cancer by regulating lipid metabolism‐related mechanisms

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