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Cell Stem Cell Jul 2020SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19...
SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.
Topics: Angiotensin-Converting Enzyme 2; Animals; Autopsy; Betacoronavirus; COVID-19; Cell Line; Coronavirus Infections; Hepatocytes; Humans; Induced Pluripotent Stem Cells; Liver; Mice; Models, Biological; Organoids; Pancreas; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; SARS-CoV-2; Tropism; Virus Internalization
PubMed: 32579880
DOI: 10.1016/j.stem.2020.06.015 -
Gastroenterology Dec 2021Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality.... (Comparative Study)
Comparative Study
BACKGROUND AND AIMS
Acute pancreatitis (AP) is an inflammatory disease with mild to severe course that is associated with local and systemic complications and significant mortality. Uncovering inflammatory pathways that lead to progression and recovery will inform ways to monitor and/or develop effective therapies.
METHODS
We performed single-cell mass Cytometry by Time Of Flight (CyTOF) analysis to identify pancreatic and systemic inflammatory signals during mild AP (referred to as AP), severe AP (SAP), and recovery using 2 independent experimental models and blood from patients with AP and recurrent AP. Flow cytometric validation of monocytes subsets identified using CyTOF analysis was performed independently.
RESULTS
Ly6C inflammatory monocytes were the most altered cells in the pancreas during experimental AP, recovery, and SAP. Deep profiling uncovered heterogeneity among pancreatic and blood monocytes and identified 7 novel subsets during AP and recovery, and 6 monocyte subsets during SAP. Notably, a dynamic shift in pancreatic CD206 macrophage population was observed during AP and recovery. Deeper profiling of the CD206 macrophage identified 7 novel subsets during AP, recovery, and SAP. Differential expression analysis of these novel monocyte and CD206 macrophage subsets revealed significantly altered surface (CD44, CD54, CD115, CD140a, CD196, podoplanin) and functional markers (interferon-γ, interleukin 4, interleukin 22, latency associated peptide-transforming growth factor-β, tumor necrosis factor-α, T-bet, RoRγt) that were associated with recovery and SAP. Moreover, a targeted functional analysis further revealed distinct expression of pro- and anti-inflammatory cytokines by pancreatic CD206 macrophage subsets as the disease either progressed or resolved. Similarly, we identified heterogeneity among circulating classical inflammatory monocytes (CD14CD16) and novel subsets in patients with AP and recurrent AP.
CONCLUSIONS
We identified several novel monocyte/macrophage subsets with unique phenotype and functional characteristics that are associated with AP, recovery, and SAP. Our findings highlight differential innate immune responses during AP progression and recovery that can be leveraged for future disease monitoring and targeting.
Topics: Animals; Biomarkers; Cell Separation; Disease Models, Animal; Female; Flow Cytometry; Humans; Immunity, Innate; Immunophenotyping; Macrophages; Mice, Inbred BALB C; Monocytes; Pancreas; Pancreatitis; Phenotype; Recovery of Function; Severity of Illness Index; Time Factors; Mice
PubMed: 34450180
DOI: 10.1053/j.gastro.2021.08.033 -
Science Signaling Oct 2022The tumor microbiome is increasingly implicated in cancer progression and resistance to chemotherapy. In pancreatic ductal adenocarcinoma (PDAC), high intratumoral loads...
The tumor microbiome is increasingly implicated in cancer progression and resistance to chemotherapy. In pancreatic ductal adenocarcinoma (PDAC), high intratumoral loads of correlate with shorter survival in patients. Here, we investigated the potential mechanisms underlying this association. We found that infection induced both normal pancreatic epithelial cells and PDAC cells to secrete increased amounts of the cytokines GM-CSF, CXCL1, IL-8, and MIP-3α. These cytokines increased proliferation, migration, and invasive cell motility in both infected and noninfected PDAC cells but not in noncancerous pancreatic epithelial cells, suggesting autocrine and paracrine signaling to PDAC cells. This phenomenon occurred in response to infection regardless of the strain and in the absence of immune and other stromal cells. Blocking GM-CSF signaling markedly limited proliferative gains after infection. Thus, infection in the pancreas elicits cytokine secretion from both normal and cancerous cells that promotes phenotypes in PDAC cells associated with tumor progression. The findings support the importance of exploring host-microbe interactions in pancreatic cancer to guide future therapeutic interventions.
Topics: Humans; Fusobacterium nucleatum; Granulocyte-Macrophage Colony-Stimulating Factor; Paracrine Communication; Interleukin-8; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Cell Proliferation; Pancreas
PubMed: 36256708
DOI: 10.1126/scisignal.abn4948 -
The American Journal of Emergency... Sep 2022
Topics: Abdomen; COVID-19; Humans; Pancreas; SARS-CoV-2
PubMed: 35644682
DOI: 10.1016/j.ajem.2022.04.023 -
Clinical and Experimental Immunology Dec 2019In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four...
In recent years, there have been exciting new insights into pathogenesis of type 1 diabetes in a number of areas of immunology. In this edition, a collection of four review articles are presented, which encompass new findings presented at the Immunology of Diabetes Society meeting in London 2018. The articles are focused particularly in 4 related areas of investigation, which include autoantibodies in type 1 diabetes, new autoantigenic targets for CD4 T cells, trafficking of immune cells to the pancreas and islet-immune interactions in the pancreas.
Topics: Autoantibodies; Autoantigens; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Humans; Islets of Langerhans; Pancreas
PubMed: 31729755
DOI: 10.1111/cei.13396 -
Gastroenterology Clinics of North... Mar 2023An association between acute pancreatitis (AP) and coronavirus disease 2019 (COVID-19) has been proposed but the mechanisms of pancreatic injury of the severe acute... (Review)
Review
An association between acute pancreatitis (AP) and coronavirus disease 2019 (COVID-19) has been proposed but the mechanisms of pancreatic injury of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and the implicative role on the development of AP are not yet fully understood. COVID-19 also imposed major challenges on pancreatic cancer management. We conducted an analysis on the mechanisms of pancreatic injury by SARS-CoV-2 and reviewed published case reports of AP attributed to COVID-19. We also examined the pandemic effect on pancreatic cancer diagnosis and management, including pancreatic surgery.
Topics: Humans; COVID-19; SARS-CoV-2; Pancreatitis; Acute Disease; Pancreas; Pancreatic Neoplasms
PubMed: 36813429
DOI: 10.1016/j.gtc.2022.12.002 -
Pancreatology : Official Journal of the... Dec 2020Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to a world-wide pandemic since its onset in December... (Review)
Review
Coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to a world-wide pandemic since its onset in December of 2019. Although, a primary respiratory pathogen, over the ensuing period, its extra-pulmonary effects have come to the forefront. The virus, having multi-organ tropism, has been shown to affect a host of other organs beyond the lung, including the pancreas. The data on pancreatic involvement by COVID-19, however, have been limited. Moreover, whether the effects on the pancreas are due to the direct effects of the virus or is just an epi-phenomenon is debatable. The prevalence of pancreatic injury and degree of injury are the other issues that need to be addressed. Pancreatic cancer has a dismal prognosis and the management of the same in the COVID era needs to be tailored assessing the risk-benefit ratio for the same. Additionally, pancreatic surgery increases not only the morbidity of the patient, but also the risk of the operator and burden on the health care system. Hence, the decision for such major procedures needs to be rationalized for optimum benefit during this pandemic. Similarly, for the endoscopist, pancreatic endoscopy needs to be carefully regulated to reduce risk to both the patient and the physician and yet deliver optimum patient care. This review gives a concise summary of various aspects of pancreatic involvement and pancreatic disease management during this pandemic.
Topics: COVID-19; Humans; Pancreas; Pancreatic Diseases; SARS-CoV-2
PubMed: 33250089
DOI: 10.1016/j.pan.2020.10.035 -
Nature Reviews. Endocrinology Aug 2022Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing... (Review)
Review
Enteroviruses are believed to trigger or accelerate islet autoimmunity in genetically susceptible individuals, thereby resulting in loss of functional insulin-producing β-cells and type 1 diabetes mellitus (T1DM). Although enteroviruses are primarily involved in acute and lytic infections in vitro and in vivo, they can also establish a persistent infection. Prospective epidemiological studies have strongly associated the persistence of enteroviruses, especially coxsackievirus B (CVB), with the appearance of islet autoantibodies and an increased risk of T1DM. CVB can persist in pancreatic ductal and β-cells, which leads to structural or functional alterations of these cells, and to a chronic inflammatory response that promotes recruitment and activation of pre-existing autoreactive T cells and β-cell autoimmune destruction. CVB persistence in other sites, such as the intestine, blood cells and thymus, has been described; these sites could serve as a reservoir for infection or reinfection of the pancreas, and this persistence could have a role in the disturbance of tolerance to β-cells. This Review addresses the involvement of persistent enterovirus infection in triggering islet autoimmunity and T1DM, as well as current strategies to control enterovirus infections for preventing or reducing the risk of T1DM onset.
Topics: Diabetes Mellitus, Type 1; Enterovirus; Enterovirus B, Human; Humans; Insulin-Secreting Cells; Prospective Studies
PubMed: 35650334
DOI: 10.1038/s41574-022-00688-1 -
Biomolecules Dec 2023Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar... (Review)
Review
Acute pancreatitis (AP) is a common acute abdomen disease characterized by the pathological activation of digestive enzymes and the self-digestion of pancreatic acinar cells. Secondary infection and sepsis are independent prognosticators for AP progression and increased mortality. Accumulating anatomical and epidemiological evidence suggests that the dysbiosis of gut microbiota affects the etiology and severity of AP through intestinal barrier disruption, local or systemic inflammatory response, bacterial translocation, and the regulatory role of microbial metabolites in AP patients and animal models. Recent studies discussing the interactions between gut microbiota and the pancreas have opened new scopes for AP, and new therapeutic interventions that target the bacteria community have received substantial attention. This review concentrates on the alterations of gut microbiota and its roles in modulating gut-pancreas axis in AP. The potential therapies of targeting microbes as well as the major challenges of applying those interventions are explored. We expect to understand the roles of microbes in AP diagnosis and treatment.
Topics: Animals; Humans; Pancreatitis; Acute Disease; Pancreas; Microbiota; Gastrointestinal Microbiome
PubMed: 38254659
DOI: 10.3390/biom14010059 -
International Journal of Molecular... Jan 2022Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the... (Review)
Review
Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the pancreas either. This review presents a summary of the molecular mechanisms involved in the development of pancreatic dysfunction during the course of COVID-19, the comparison of the effects of non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on pancreatic function, and a summary of how drugs used in COVID-19 treatment may affect this organ. It appears that diabetes is not only a condition that predisposes a patient to suffer from more severe COVID-19, but it may also develop as a consequence of infection with this virus. Some SARS-CoV-2 inpatients experience acute pancreatitis due to direct infection of the tissue with the virus or due to systemic multiple organ dysfunction syndrome (MODS) accompanied by elevated levels of amylase and lipase. There are also reports that reveal a relationship between the development and treatment of pancreatic cancer and SARS-CoV-2 infection. It has been postulated that evaluation of pancreatic function should be increased in post-COVID-19 patients, both adults and children.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Diabetes Complications; Diabetes Mellitus; Humans; Middle East Respiratory Syndrome Coronavirus; Pancreas; Pancreatic Neoplasms; Pancreatitis; Severe acute respiratory syndrome-related coronavirus; Serine Endopeptidases; Sodium-Hydrogen Exchangers; COVID-19 Drug Treatment
PubMed: 35055050
DOI: 10.3390/ijms23020864