Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes

Zakharov, Pavel N.; Hu, Hao; Wan, Xiaoxiao; Unanue, Emil R.

doi:10.1084/jem.20192362

Cited by 86 publications

(110 citation statements)

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“…However, a higher heterogeneity is expected to be present. Indeed, advanced single-cell sequencing in islets from NOD mice identified different subsets of islet macrophages including anti-and pro-inflammatory populations at all stages of disease progression [49]. Similar levels of complexity are expected in T2D-associated low-grade chronic inflammation.…”

Section: Discussionmentioning

confidence: 71%

“…Bulk RNA sequencing was performed in the macrophage population sorted from islets of 2-, 4-, 8-, and 12-week-old NOD mice to gather deep transcriptional data. This analysis showed an upregulation of genes downstream of IFN-γ signalling and of IL-2/STAT5 and IL-6/STAT3 pathways together with the progression of the disease [49]. Most of the activated genes were involved in the antigen presentation and production of pro-inflammatory cytokines.…”

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 90%

“…One report showed that depletion of resident macrophages in 3-week-old NOD mice using a monoclonal antibody against the CSF-1 receptor leads to a reduction in infiltrating T-cells and significantly decreases diabetes development [48]. In a very recent report, single-cell analysis was performed in order to characterise the cell types present during the progression of insulitis in NOD mice [49]. Bulk RNA sequencing was performed in the macrophage population sorted from islets of 2-, 4-, 8-, and 12-week-old NOD mice to gather deep transcriptional data.…”

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 99%

“…While bulk RNA sequencing pointed to a major proinflammatory shift in macrophage activation state, single-cell sequencing revealed the presence of five main subsets of macrophage populations expressing specific markers. Specific transcriptomic signatures were found for two subpopulations with stable features throughout disease progression and self-renewal capacity (Mac-1;Apoe and Mac-5;Stmn1), two sets of macrophages with increased pro-inflammatory activity (Mac-2;Atf3 and Mac-3;CXCL9), and one presenting increased apoptotic cell clearance, efferocytosis, and antiinflammatory properties (Mac-4;Prdx1) [49]. This very advanced work suggested that despite an overall pro-inflammatory progression of the macrophage phenotype during insulitis, these cells may exert several different functions.…”

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 99%

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Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

Cristina

Regazzi

2021

IJMS

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Macrophages are highly heterogeneous and plastic immune cells with peculiar characteristics dependent on their origin and microenvironment. Following pathogen infection or damage, circulating monocytes can be recruited in different tissues where they differentiate into macrophages. Stimuli present in the surrounding milieu induce the polarisation of macrophages towards a pro-inflammatory or anti-inflammatory profile, mediating inflammatory or homeostatic responses, respectively. However, macrophages can also derive from embryonic hematopoietic precursors and reside in specific tissues, actively participating in the development and the homeostasis in physiological conditions. Pancreatic islet resident macrophages are present from the prenatal stages onwards and show specific surface markers and functions. They localise in close proximity to β-cells, being exquisite sensors of their secretory ability and viability. Over the years, the crucial role of macrophages in β-cell differentiation and homeostasis has been highlighted. In addition, macrophages are emerging as central players in the initiation of autoimmune insulitis in type 1 diabetes and in the low-grade chronic inflammation characteristic of obesity and type 2 diabetes pathogenesis. The present work reviews the current knowledge in the field, with a particular focus on the mechanisms of communication between β-cells and macrophages that have been described so far.

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Section: Discussionmentioning

confidence: 71%

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 90%

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 99%

Section: Role Of Macrophages In Type 1 Diabetesmentioning

confidence: 99%

See 2 more Smart Citations

Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

Cristina

Regazzi

2021

IJMS

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“…Expansions of islet antigen-reactive T cells have been documented in the blood of both T1D cases and healthy controls (6) whereas age-dependent changes in immune phenotype at diagnosis (7) have underlined the complexity of studying disease in the context of a developing immune system. Within the pancreas, longitudinal single-cell RNAseq analysis has indicated complex, dynamic changes in infiltrating immune cell populations (8). Although comparable study of human tissue is not possible, pseudotime mass cytometry of pancreatic tissue from T1D-diagnosed donors has illustrated an influx of cytotoxic and helper T cells associated with reductions in beta cell mass (9).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression

et al. 2021

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Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet β cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model’s predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.

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Single‐Cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

et al. 2022

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is considered as an essential pathophysiologic factor and target in the context of MI. However, numerous clinical trials of post-MI immunomodulating/anti-inflammatory targets have shown inconclusive and controversial results. [3] Hence, studies are needed to understand what, how, and in what time frame the immune system is activated, providing a basis for modulating the immune-inflammatory mechanisms underlying the myocardial healing process.Cardiac immune cells are highly heterogeneous, and their activation in the progression of MI is distinct. [4] Some cell types such as macrophages and monocytes, which play a central role in multiple pathophysiological processes of MI, are comprised of diverse subsets because of their different origins and functions. [5] However, much less is known about the complex diversity of cardiac immunity. Recently, an innovative high-throughput technology, single-cell RNA sequencing (scRNA-seq), has increased our understanding of the major immune cell types in the mammalian heart and their dynamics during disease progression. Dick et al. [6] identified functionally distinct cardiac macrophage subsets that are hierarchically replaced by monocytes after infarction. Vafadarnejad et al. [7] revealed temporal diversity and local transition of neutrophils within the ischemic tissue. Moreover, Farbehi et al. [8] described the heterogeneity and dynamics of several cardiac immune Myocardial infarction (MI) is strongly associated with the temporal regulation of cardiac immunity. However, a variety of current clinical trials have failed because of the lack of post-MI immunomodulating/anti-inflammatory targets. Single-cell RNA sequencing analysis of the cardiac Cd45 + immune cell at 0, 3, 7, and 14 d after injury in a mouse left anterior descending coronary artery ligation model is performed. Major immune cell populations, distinct subsets, and dynamic changes are identified. Macrophages (Mø) are most abundant, peaking at 3 d after infarction. Mø-5 and Mø-6 are the predominant infiltrated subsets at this time point, with strong expression of inflammatory factors. Further analysis demonstrates that suppressing these sets attenuated pathological MI progression by preventing subsequent leukocyte extravasation and adverse remodeling. Abundant apoptotic neutrophils and a profibrotic macrophage subset on days 7 and 14, respectively, are also detected. These results provide a basis for developing cell type-and time-specific interventions in MI.The ORCID identification number(s) for the author(s) of this article can be found under https://doi.org/10.1002/smtd.202100752.

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Single-cell RNA sequencing of murine islets shows high cellular complexity at all stages of autoimmune diabetes

Cited by 86 publications

References 100 publications

Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression

Single‐Cell RNA Sequencing Reveals the Temporal Diversity and Dynamics of Cardiac Immunity after Myocardial Infarction

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