-
Frontiers in Immunology 2022Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role...
Acute pancreatitis (AP) is a common cause of a clinically acute abdomen. Crosstalk between acinar cells and leukocytes (especially macrophages) plays an important role in the development of AP. However, the mechanism mediating the interaction between acinar cells and macrophages is still unclear. This study was performed to explore the role of acinar cell extracellular vesicles (EVs) in the crosstalk between acinar cells and macrophages involved in the pathogenesis of AP. EVs derived from caerulein-treated acinar cells induced macrophage infiltration and aggravated pancreatitis in an AP rat model. Further research showed that acinar cell-derived EV miR-183-5p led to M1 macrophage polarization by downregulating forkhead box protein O1 (FoxO1), and a dual-luciferase reporter assay confirmed that FoxO1 was directly inhibited by miR-183-5p. In addition, acinar cell-derived EV miR-183-5p reduced macrophage phagocytosis. Acinar cell-derived EV miR-183-5p promoted the pancreatic infiltration of M1 macrophages and increased local and systemic damage . Subsequently, miR-183-5p overexpression in macrophages induced acinar cell damage and trypsin activation, thus further exacerbating the disease. In clinical samples, elevated miR-183-5p levels were detected in serum EVs and positively correlated with the severity of AP. EV miR-183-5p might play an important role in the development of AP by facilitating M1 macrophage polarization, providing a new insight into the diagnosis and targeted management of pancreatitis. Graphical abstract of the present study. In our caerulein-induced AP model, miR-183-5p was upregulated in injured acinar cells and transported by EVs to macrophages. miR-183-5p could induce M1 macrophage polarization through downregulation of FoxO1 and the release of inflammatory cytokines, which could aggravate AP-related injuries. Therefore, a vicious cycle might exist between injured ACs and M1 macrophage polarization, which is fulfilled by EV-transported miR-183-5p, leading to sustainable and progressive AP-related injuries.
Topics: Acinar Cells; Acute Disease; Animals; Ceruletide; Down-Regulation; Extracellular Vesicles; Macrophages; MicroRNAs; Nerve Tissue Proteins; Pancreatitis; Rats
PubMed: 35911777
DOI: 10.3389/fimmu.2022.869207 -
Pancreas Apr 2019Acute pancreatitis (AP) is a potentially lethal inflammatory disease that lacks specific therapy. Damaged pancreatic acinar cells are believed to be the site of AP... (Review)
Review
Acute pancreatitis (AP) is a potentially lethal inflammatory disease that lacks specific therapy. Damaged pancreatic acinar cells are believed to be the site of AP initiation. The primary function of these cells is the synthesis, storage, and export of digestive enzymes. Beginning in the endoplasmic reticulum and ending with secretion of proteins stored in zymogen granules, distinct pancreatic organelles use ATP produced by mitochondria to move and modify nascent proteins through sequential vesicular compartments. Compartment-specific accessory proteins concentrate cargo and promote vesicular budding, targeting, and fusion. The autophagy-lysosomal-endosomal pathways maintain acinar cell homeostasis by removing damaged/dysfunctional organelles and recycling cell constituents for substrate and energy. Here, we discuss studies in experimental and genetic AP models, primarily from our groups, which show that acinar cell injury is mediated by distinct mechanisms of organelle dysfunction involved in protein synthesis and trafficking, secretion, energy generation, and autophagy. These early AP events (often first manifest by abnormal cytosolic Ca signaling) in the acinar cell trigger the inflammatory and cell death responses of pancreatitis. Manifestations of acinar cell organelle disorders are also prominent in human pancreatitis. Our findings suggest that targeting specific mediators of organelle dysfunction could reduce disease severity.
Topics: Acinar Cells; Acute Disease; Autophagy; Endoplasmic Reticulum; Endosomes; Homeostasis; Humans; Lysosomes; Pancreatitis; Secretory Vesicles
PubMed: 30973461
DOI: 10.1097/MPA.0000000000001298 -
Journal of Oral Science Aug 2019Salivary gland atrophy and consequent hyposalivation are serious problems in clinical dentistry, as saliva regulates the environment of the oral cavity. To clarify the...
Salivary gland atrophy and consequent hyposalivation are serious problems in clinical dentistry, as saliva regulates the environment of the oral cavity. To clarify the mechanisms underlying salivary gland dysfunction, a system for primary culture of parotid acinar cells has been established. It has been reported previously that the process of cell isolation from parotid glands triggers stress signaling mediated by Src and p38 mitogen-activated protein (MAP) kinase (p38), leading to dedifferentiation of acinar cells, and that an nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor suppresses this activation of Src and p38, suggesting that reactive oxygen species initiate the dedifferentiation signal. The present study examined the effect of a free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (also termed MCI-186 or edaravone), on activation of the stress signal and the secretory function of parotid acinar cells. Activation of p38 during cell isolation was suppressed by addition of MCI-186. The retention of the activity of amylase, a major salivary protein, and the number of amylase-containing secretory granules were improved by isolation and culture in the presence of MCI-186. In addition, calcium elevation upon stimulation with a muscarinic agonist was higher in MCI-186-treated cells than in untreated cells. These results suggest that MCI-186 (edaravone) is a promising agent for prevention of salivary gland dysfunction.
Topics: Acinar Cells; Edaravone; Free Radical Scavengers; Parotid Gland; Signal Transduction
PubMed: 31378753
DOI: 10.2334/josnusd.18-0405 -
ELife Oct 2017Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive...
Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.
Topics: Acinar Cells; Animals; Carcinogenesis; Cell Communication; Epithelial Cells; ErbB Receptors; Mice; Mitogen-Activated Protein Kinase Kinases; Myeloid Cells; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 28980940
DOI: 10.7554/eLife.27388 -
Advanced Healthcare Materials Apr 2022Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro....
Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)-Degradable Hydrogels to Maintain Tissue Structure and Function.
Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, is investigated. This isolation approach yields AIDUCs that maintain many of the cell-cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promotes self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, is detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirms expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux is observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia is observed within SGm, it is reduced compared to previous reports. In conclusion, cell-cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.
Topics: Acinar Cells; Hydrogels; Matrix Metalloproteinases; Salivary Glands
PubMed: 34994104
DOI: 10.1002/adhm.202101948 -
Cell Reports Dec 2023While programmed cell death plays important roles during morphogenetic stages of development, post-differentiation organ growth is considered an efficient process...
While programmed cell death plays important roles during morphogenetic stages of development, post-differentiation organ growth is considered an efficient process whereby cell proliferation increases cell number. Here we demonstrate that early postnatal growth of the pancreas unexpectedly involves massive acinar cell elimination. Measurements of cell proliferation and death in the human pancreas in comparison to the actual increase in cell number predict daily elimination of 0.7% of cells, offsetting 88% of cell formation over the first year of life. Using mouse models, we show that death is associated with mitosis, through a failure of dividing cells to generate two viable daughters. In p53-deficient mice, acinar cell death and proliferation are reduced, while organ size is normal, suggesting that p53-dependent developmental apoptosis triggers compensatory proliferation. We propose that excess cell turnover during growth of the pancreas, and presumably other organs, facilitates robustness to perturbations and supports maintenance of tissue architecture.
Topics: Animals; Mice; Humans; Acinar Cells; Tumor Suppressor Protein p53; Pancreas; Cell Differentiation; Apoptosis
PubMed: 37995187
DOI: 10.1016/j.celrep.2023.113457 -
Cellular and Molecular Gastroenterology... 2022Pancreatic ductal adenocarcinoma (PDAC) is a devastating type of cancer. While many studies have shed light into the pathobiology of PDAC, the nature of PDAC's cell of... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a devastating type of cancer. While many studies have shed light into the pathobiology of PDAC, the nature of PDAC's cell of origin remains under debate. Studies in adult pancreatic tissue have unveiled a remarkable exocrine cell plasticity including transitional states, mostly exemplified by acinar to ductal cell metaplasia, but also with recent evidence hinting at duct to basal cell transitions. Single-cell RNA sequencing has further revealed intrapopulation heterogeneity among acinar and duct cells. Transcriptomic and epigenomic relationships between these exocrine cell differentiation states and PDAC molecular subtypes have started to emerge, suggesting different ontogenies for different tumor subtypes. This review sheds light on these diverse aspects with particular focus on studies with human cells. Understanding the "masked ball" of exocrine cells at origin of PDAC and leaving behind the binary acinar vs duct cell classification may significantly advance our insights in PDAC biology.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Cell Plasticity; Humans; Pancreatic Neoplasms
PubMed: 34875393
DOI: 10.1016/j.jcmgh.2021.11.010 -
Cell Stem Cell Jun 2021In this issue of Cell Stem Cell, Huang et al. (2021) and Breunig et al. (2021) developed human stem-cell-derived organoid culture systems to recapitulate pancreatic...
In this issue of Cell Stem Cell, Huang et al. (2021) and Breunig et al. (2021) developed human stem-cell-derived organoid culture systems to recapitulate pancreatic acinar and ductal lineages. This provides opportunities to study cellular plasticity and transformation in pancreatic cancer initiation and progression.
Topics: Acinar Cells; Humans; Organoids; Pancreas; Pancreas, Exocrine; Pancreatic Ducts; Pancreatic Neoplasms; Pluripotent Stem Cells
PubMed: 34087158
DOI: 10.1016/j.stem.2021.05.006 -
ELife Jul 2018Chromatin remodeling processes can drive acinar cell fate decisions.
Chromatin remodeling processes can drive acinar cell fate decisions.
Topics: Acinar Cells; Cell Differentiation; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; Genes, ras
PubMed: 30014853
DOI: 10.7554/eLife.38967 -
Biochimica Et Biophysica Acta Jun 2016In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by...
In a recent study we explored Group-1-p21-activated kinases (GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-, Src- and small-GTPase-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2's role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini, PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin (CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs-inhibitor and infection with a PAK2-dominant negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK's effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.
Topics: Acinar Cells; Animals; Cell Death; Enzyme Activation; Male; Pancreas; Pancreatitis; Rats; Rats, Sprague-Dawley; Signal Transduction; p21-Activated Kinases
PubMed: 26912410
DOI: 10.1016/j.bbadis.2016.02.008