RESUMEN
Ahmed and colleagues recently described a novel hybrid lymphocyte expressing both a B and T cell receptor, termed double expresser (DE) cells. DE cells in blood of type 1 diabetes (T1D) subjects were present at increased numbers and enriched for a public B cell clonotype. Here, we attempted to reproduce these findings. While we could identify DE cells by flow cytometry, we found no association between DE cell frequency and T1D status. We were unable to identify the reported public B cell clone, or any similar clone, in bulk B cells or sorted DE cells from T1D subjects or controls. We also did not observe increased usage of the public clone VH or DH genes in B cells or in sorted DE cells. Taken together, our findings suggest that DE cells and their alleged public clonotype are not enriched in T1D. This Matters Arising paper is in response to Ahmed et al. (2019), published in Cell. See also the response by Ahmed et al. (2021), published in this issue.
Asunto(s)
Diabetes Mellitus Tipo 1 , Linfocitos B , Células Clonales , Diabetes Mellitus Tipo 1/genética , Citometría de Flujo , Humanos , Receptores de Antígenos de Linfocitos TRESUMEN
The pancreatic islets of Langerhans regulate glucose homeostasis. The loss of insulin-producing ß cells within islets results in diabetes, and islet transplantation from cadaveric donors can cure the disease. In vitro production of whole islets, not just ß cells, will benefit from a better understanding of endocrine differentiation and islet morphogenesis. We used single-cell mRNA sequencing to obtain a detailed description of pancreatic islet development. Contrary to the prevailing dogma, we find islet morphology and endocrine differentiation to be directly related. As endocrine progenitors differentiate, they migrate in cohesion and form bud-like islet precursors, or "peninsulas" (literally "almost islands"). α cells, the first to develop, constitute the peninsular outer layer, and ß cells form later, beneath them. This spatiotemporal collinearity leads to the typical core-mantle architecture of the mature, spherical islet. Finally, we induce peninsula-like structures in differentiating human embryonic stem cells, laying the ground for the generation of entire islets in vitro.
Asunto(s)
Islotes Pancreáticos/citología , Islotes Pancreáticos/embriología , Animales , Diferenciación Celular , Células Cultivadas , Células Madre Embrionarias Humanas/citología , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/citología , Islotes Pancreáticos/metabolismo , Trasplante de Islotes Pancreáticos/métodos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Morfogénesis , Páncreas/citologíaRESUMEN
Much of current molecular and cell biology research relies on the ability to purify cell types by fluorescence-activated cell sorting (FACS). FACS typically relies on the ability to label cell types of interest with antibodies or fluorescent transgenic constructs. However, antibody availability is often limited, and genetic manipulation is labor intensive or impossible in the case of primary human tissue. To date, no systematic method exists to enrich for cell types without a priori knowledge of cell-type markers. Here, we propose GateID, a computational method that combines single-cell transcriptomics with FACS index sorting to purify cell types of choice using only native cellular properties such as cell size, granularity, and mitochondrial content. We validate GateID by purifying various cell types from zebrafish kidney marrow and the human pancreas to high purity without resorting to specific antibodies or transgenes.
Asunto(s)
Separación Celular/métodos , Citometría de Flujo/métodos , Programas Informáticos , Transcriptoma , Animales , Humanos , Riñón/citología , Páncreas/citología , Análisis de la Célula Individual , Pez Cebra/anatomía & histologíaRESUMEN
Lymph nodes (LNs) are critical sites for shaping tissue-specific adaptive immunity. However, the impact of LN sharing between multiple organs on such tailoring is less understood. Here, we describe the drainage hierarchy of the pancreas, liver, and the upper small intestine (duodenum) into three murine LNs. Migratory dendritic cells (migDCs), key in instructing adaptive immune outcome, exhibited stronger pro-inflammatory signatures when originating from the pancreas or liver than from the duodenum. Qualitatively different migDC mixing in each shared LN influenced pancreatic ß-cell-reactive T cells to acquire gut-homing and tolerogenic phenotypes proportional to duodenal co-drainage. However, duodenal viral infections rendered non-intestinal migDCs and ß-cell-reactive T cells more pro-inflammatory in all shared LNs, resulting in elevated pancreatic islet lymphocyte infiltration. Our study uncovers immune crosstalk through LN co-drainage as a powerful force regulating pancreatic autoimmunity.
Asunto(s)
Autoinmunidad , Páncreas , Ratones , Animales , Páncreas/patología , Hígado , Linfocitos T , Ganglios LinfáticosRESUMEN
The recent discovery that genetically modified α cells can regenerate and convert into ß-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-ß-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into ß-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated ß-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in ß-like cell counts, suggestive of α-to-ß-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated ß-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Células Secretoras de Glucagón/citología , Células Secretoras de Insulina/citología , Ácido gamma-Aminobutírico/administración & dosificación , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus/inducido químicamente , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patología , Células Secretoras de Glucagón/efectos de los fármacos , Humanos , Islotes Pancreáticos/citología , Masculino , Ratones , Proteínas del Tejido Nervioso , Ratas , Ratas Wistar , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
As organisms age, cells accumulate genetic and epigenetic errors that eventually lead to impaired organ function or catastrophic transformation such as cancer. Because aging reflects a stochastic process of increasing disorder, cells in an organ will be individually affected in different ways, thus rendering bulk analyses of postmitotic adult cells difficult to interpret. Here, we directly measure the effects of aging in human tissue by performing single-cell transcriptome analysis of 2,544 human pancreas cells from eight donors spanning six decades of life. We find that islet endocrine cells from older donors display increased levels of transcriptional noise and potential fate drift. By determining the mutational history of individual cells, we uncover a novel mutational signature in healthy aging endocrine cells. Our results demonstrate the feasibility of using single-cell RNA sequencing (RNA-seq) data from primary cells to derive insights into genetic and transcriptional processes that operate on aging human tissue.
Asunto(s)
Envejecimiento/patología , Senescencia Celular , Mutación , Páncreas/patología , Análisis de la Célula Individual , Adulto , Niño , Preescolar , Humanos , Lactante , Persona de Mediana Edad , Páncreas/citología , Páncreas/fisiología , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ARN , Transcripción GenéticaRESUMEN
Stellate cells are resident lipid-storing cells of the pancreas and liver that transdifferentiate to a myofibroblastic state in the context of tissue injury. Beyond having roles in tissue homeostasis, stellate cells are increasingly implicated in pathological fibrogenic and inflammatory programs that contribute to tissue fibrosis and that constitute a growth-permissive tumor microenvironment. Although the capacity of stellate cells for extracellular matrix production and remodeling has long been appreciated, recent research efforts have demonstrated diverse roles for stellate cells in regulation of epithelial cell fate, immune modulation, and tissue health. Our present understanding of stellate cell biology in health and disease is discussed here, as are emerging means to target these multifaceted cells for therapeutic benefit.
Asunto(s)
Células Estrelladas Hepáticas/metabolismo , Inflamación/genética , Neoplasias/genética , Células Estrelladas Pancreáticas/metabolismo , Transdiferenciación Celular/genética , Células Estrelladas Hepáticas/patología , Humanos , Inflamación/patología , Hígado/metabolismo , Hígado/patología , Miofibroblastos/metabolismo , Miofibroblastos/patología , Neoplasias/patología , Páncreas/lesiones , Páncreas/metabolismo , Páncreas/patología , Células Estrelladas Pancreáticas/patología , Microambiente Tumoral/genética , Cicatrización de HeridasRESUMEN
Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Proliferación Celular , Neoplasias Pancreáticas/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Neurregulina-1/genética , Neurregulina-1/metabolismoRESUMEN
Genetics is a major determinant of susceptibility to autoimmune disorders. Here, we examined whether genome organization provides resilience or susceptibility to sequence variations, and how this would contribute to the molecular etiology of an autoimmune disease. We generated high-resolution maps of linear and 3D genome organization in thymocytes of NOD mice, a model of type 1 diabetes (T1D), and the diabetes-resistant C57BL/6 mice. Multi-enhancer interactions formed at genomic regions harboring genes with prominent roles in T cell development in both strains. However, diabetes risk-conferring loci coalesced enhancers and promoters in NOD, but not C57BL/6 thymocytes. 3D genome mapping of NODxC57BL/6 F1 thymocytes revealed that genomic misfolding in NOD mice is mediated in cis. Moreover, immune cells infiltrating the pancreas of humans with T1D exhibited increased expression of genes located on misfolded loci in mice. Thus, genetic variation leads to altered 3D chromatin architecture and associated changes in gene expression that may underlie autoimmune pathology.
Asunto(s)
Cromatina/metabolismo , Diabetes Mellitus Tipo 1/genética , Predisposición Genética a la Enfermedad/genética , Timocitos/patología , Animales , Factor de Unión a CCCTC/metabolismo , Mapeo Cromosómico , Diabetes Mellitus Tipo 1/patología , Epigénesis Genética , Expresión Génica , Sitios Genéticos/genética , Variación Genética , Genoma/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Páncreas/patología , Secuencias Reguladoras de Ácidos NucleicosRESUMEN
In the adult mammalian body, self-renewal of tissue stem cells is regulated by extracellular niche environments in response to the demands of tissue organization. Intestinal stem cells expressing Lgr5 constantly self-renew in their specific niche at the crypt bottom to maintain rapid turnover of the epithelium. Niche-regulated stem cell self-renewal is perturbed in several mouse genetic models and during human tumorigenesis, suggesting roles for EGF, Wnt, BMP/TGF-ß, and Notch signaling. In vitro niche reconstitution capitalizing on this knowledge has enabled the growth of single intestinal stem cells into mini-gut epithelial organoids comprising Lgr5(+) stem cells and all types of differentiated lineages. The mini-gut organoid culture platform is applicable to various types of digestive tissue epithelium from multiple species. The mechanism of self-renewal in organoids provides novel insights for organogenesis, regenerative medicine, and tumorigenesis of the digestive system.
Asunto(s)
Intestinos/fisiología , Organoides/fisiología , Regeneración/fisiología , Nicho de Células Madre/fisiología , Células Madre/fisiología , Animales , Carcinogénesis/patología , Epitelio/fisiología , Humanos , Transducción de Señal/fisiologíaRESUMEN
Cancer cells adapt their metabolism to support elevated energetic and anabolic demands of proliferation. Folate-dependent one-carbon metabolism is a critical metabolic process underpinning cellular proliferation supplying carbons for the synthesis of nucleotides incorporated into DNA and RNA. Recent research has focused on the nutrients that supply one-carbons to the folate cycle, particularly serine. Tryptophan is a theoretical source of one-carbon units through metabolism by IDO1, an enzyme intensively investigated in the context of tumor immune evasion. Using in vitro and in vivo pancreatic cancer models, we show that IDO1 expression is highly context dependent, influenced by attachment-independent growth and the canonical activator IFNγ. In IDO1-expressing cancer cells, tryptophan is a bona fide one-carbon donor for purine nucleotide synthesis in vitro and in vivo. Furthermore, we show that cancer cells release tryptophan-derived formate, which can be used by pancreatic stellate cells to support purine nucleotide synthesis.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Neoplasias Pancreáticas/genética , Células Estrelladas Pancreáticas/metabolismo , Escape del Tumor/efectos de los fármacos , Aloinjertos , Animales , Antineoplásicos/farmacología , Carbono/inmunología , Carbono/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Línea Celular Tumoral , Formiatos/inmunología , Formiatos/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Interferón gamma/genética , Interferón gamma/inmunología , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Oximas/farmacología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/inmunología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/inmunología , Serina/inmunología , Serina/metabolismo , Serina/farmacología , Transducción de Señal , Sulfonamidas/farmacología , Triptófano/inmunología , Triptófano/metabolismo , Triptófano/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/inmunologíaRESUMEN
Multiple transcription factors have been shown to promote pancreatic ß-cell differentiation, yet much less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrinogenesis in the embryonic pancreas. However, pancreatic Rest knockout mice failed to show abnormal numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we observed a marked increase in pancreatic endocrine cell formation. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts and induced ß-cell-specific genes in human adult duct-derived organoids. We also defined genomic sites that are bound and repressed by REST in the embryonic pancreas. Our findings show that REST-dependent inhibition ensures a balanced production of endocrine cells from embryonic pancreatic progenitors.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Pez Cebra , Animales , Diferenciación Celular/genética , Ratones , Organogénesis/genética , Páncreas , Pez Cebra/genéticaRESUMEN
The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic ß cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human ß cells remain unknown. Here, we show that shRNA-mediated SIX2 or SIX3 suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that SIX2 and SIX3 regulate distinct targets. Loss of SIX2 markedly impaired expression of genes governing ß-cell insulin processing and output, glucose sensing, and electrophysiology, while SIX3 loss led to inappropriate expression of genes normally expressed in fetal ß cells, adult α cells, and other non-ß cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, ß cells from diabetic humans with impaired insulin secretion also had reduced SIX2 transcript levels. Revealing how SIX2 and SIX3 govern functional maturation and maintain developmental fate in native human ß cells should advance ß-cell replacement and other therapeutic strategies for diabetes.
Asunto(s)
Diferenciación Celular/genética , Proteínas del Ojo/metabolismo , Regulación de la Expresión Génica/genética , Proteínas de Homeodominio/metabolismo , Células Secretoras de Insulina/citología , Proteínas del Tejido Nervioso/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Humanos , Secreción de Insulina/genética , ARN Interferente Pequeño/metabolismo , Transcriptoma , Proteína Homeobox SIX3RESUMEN
Multiple G protein-coupled receptors (GPCRs) are expressed in pancreatic islet cells, but the majority have unknown functions. We observed specific GPCRs localized to primary cilia, a prominent signaling organelle, in pancreatic α and ß cells. Loss of cilia disrupts ß-cell endocrine function, but the molecular drivers are unknown. Using functional expression, we identified multiple GPCRs localized to cilia in mouse and human islet α and ß cells, including FFAR4, PTGER4, ADRB2, KISS1R, and P2RY14. Free fatty acid receptor 4 (FFAR4) and prostaglandin E receptor 4 (PTGER4) agonists stimulate ciliary cAMP signaling and promote glucagon and insulin secretion by α- and ß-cell lines and by mouse and human islets. Transport of GPCRs to primary cilia requires TULP3, whose knockdown in primary human and mouse islets relocalized ciliary FFAR4 and PTGER4 and impaired regulated glucagon or insulin secretion, without affecting ciliary structure. Our findings provide index evidence that regulated hormone secretion by islet α and ß cells is controlled by ciliary GPCRs providing new targets for diabetes.
Asunto(s)
Células Secretoras de Insulina , Islotes Pancreáticos , Animales , Glucagón/metabolismo , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Receptores Acoplados a Proteínas G/genéticaRESUMEN
Proper embryonic development depends on the timely progression of a genetic program. One of the key mechanisms for achieving precise control of developmental timing is to use gene expression oscillations. In this Review, we examine how gene expression oscillations encode temporal information during vertebrate embryonic development by discussing the gene expression oscillations occurring during somitogenesis, neurogenesis, myogenesis and pancreas development. These oscillations play important but varied physiological functions in different contexts. Oscillations control the period of somite formation during somitogenesis, whereas they regulate the proliferation-to-differentiation switch of stem cells and progenitor cells during neurogenesis, myogenesis and pancreas development. We describe the similarities and differences of the expression pattern in space (i.e. whether oscillations are synchronous or asynchronous across neighboring cells) and in time (i.e. different time scales) of mammalian Hes/zebrafish Her genes and their targets in different tissues. We further summarize experimental evidence for the functional role of their oscillations. Finally, we discuss the outstanding questions for future research.
Asunto(s)
Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Somitos , Animales , Desarrollo Embrionario/genética , Humanos , Somitos/metabolismo , Somitos/embriología , Desarrollo de Músculos/genética , Neurogénesis/genética , Neurogénesis/fisiología , Páncreas/embriología , Páncreas/metabolismo , Diferenciación Celular/genéticaRESUMEN
The autonomic nervous system innervates the pancreas by sympathetic, parasympathetic and sensory branches during early organogenesis, starting with neural crest cell invasion and formation of an intrinsic neuronal network. Several studies have demonstrated that signals from pancreatic neural crest cells direct pancreatic endocrinogenesis. Likewise, autonomic neurons have been shown to regulate pancreatic islet formation, and have also been implicated in type I diabetes. Here, we provide an overview of recent progress in mapping pancreatic innervation and understanding the interactions between pancreatic neurons, epithelial morphogenesis and cell differentiation. Finally, we discuss pancreas innervation as a factor in the development of diabetes.
Asunto(s)
Diabetes Mellitus , Islotes Pancreáticos , Humanos , Diferenciación Celular , Organogénesis , PáncreasRESUMEN
The orphan nuclear receptor SHP (small heterodimer partner) is a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver; however, its function in other tissues is poorly understood. Here, we report an unexpected role for SHP in the exocrine pancreas as a modulator of the endoplasmic reticulum (ER) stress response. SHP expression is induced in acinar cells in response to ER stress and regulates the protein stability of the spliced form of X-box-binding protein 1 (XBP1s), a key mediator of ER stress response. Loss of SHP reduces XBP1s protein level and transcriptional activity, which in turn attenuates the ER stress response during the fasting-feeding cycle. Consequently, SHP-deficient mice also are more susceptible to cerulein-induced pancreatitis. Mechanistically, we show that SHP physically interacts with the transactivation domain of XBP1s, thereby inhibiting the polyubiquitination and degradation of XBP1s by the Cullin3-SPOP (speckle-type POZ protein) E3 ligase complex. Together, our data implicate SHP in governing ER homeostasis and identify a novel posttranslational regulatory mechanism for the key ER stress response effector XBP1.
Asunto(s)
Estrés del Retículo Endoplásmico/genética , Proteolisis , Receptores Citoplasmáticos y Nucleares/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Células Acinares/metabolismo , Animales , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Páncreas Exocrino/metabolismo , Pancreatitis/genética , Empalme de Proteína , Estabilidad Proteica , Receptores Citoplasmáticos y Nucleares/deficiencia , Receptores Citoplasmáticos y Nucleares/genética , Ubiquitinación/genéticaRESUMEN
Maintaining blood glucose at an appropriate physiological level requires precise coordination of multiple organs and tissues. The vagus nerve bidirectionally connects the central nervous system with peripheral organs crucial to glucose mobilization, nutrient storage, and food absorption, thereby presenting a key pathway for the central control of blood glucose levels. However, the precise mechanisms by which vagal populations that target discrete tissues participate in glucoregulation are much less clear. Here we review recent advances unraveling the cellular identity, neuroanatomical organization, and functional contributions of both vagal efferents and vagal afferents in the control of systemic glucose metabolism. We focus on their involvement in relaying glucoregulatory cues from the brain to peripheral tissues, particularly the pancreatic islet, and by sensing and transmitting incoming signals from ingested food to the brain. These recent findings - largely driven by advances in viral approaches, RNA sequencing, and cell-type selective manipulations and tracings - have begun to clarify the precise vagal neuron populations involved in the central coordination of glucose levels, and raise interesting new possibilities for the treatment of glucose metabolism disorders such as diabetes.
Asunto(s)
Glucemia , Nervio Vago , Glucemia/metabolismo , Nervio Vago/metabolismo , Glucosa/metabolismoRESUMEN
Hormone secretion from pancreatic islets is essential for glucose homeostasis, and loss or dysfunction of islet cells is a hallmark of type 2 diabetes. Maf transcription factors are crucial for establishing and maintaining adult endocrine cell function. However, during pancreas development, MafB is not only expressed in insulin- and glucagon-producing cells, but also in Neurog3+ endocrine progenitor cells, suggesting additional functions in cell differentiation and islet formation. Here, we report that MafB deficiency impairs ß cell clustering and islet formation, but also coincides with loss of neurotransmitter and axon guidance receptor gene expression. Moreover, the observed loss of nicotinic receptor gene expression in human and mouse ß cells implied that signaling through these receptors contributes to islet cell migration/formation. Inhibition of nicotinic receptor activity resulted in reduced ß cell migration towards autonomic nerves and impaired ß cell clustering. These findings highlight a novel function of MafB in controlling neuronal-directed signaling events required for islet formation.
Asunto(s)
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Islotes Pancreáticos , Ratones , Adulto , Animales , Humanos , Glucagón/genética , Glucagón/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Islotes Pancreáticos/metabolismo , Insulina/metabolismo , Páncreas/metabolismo , Factor de Transcripción MafB/genética , Factor de Transcripción MafB/metabolismoRESUMEN
Tumor-associated macrophages (TAMs) are essential components of the cancer microenvironment and play critical roles in the regulation of tumor progression. Optimal therapeutic intervention requires in-depth understanding of the sources that sustain macrophages in malignant tissues. In this study, we investigated the ontogeny of TAMs in murine pancreatic ductal adenocarcinoma (PDAC) models. We identified both inflammatory monocytes and tissue-resident macrophages as sources of TAMs. Unexpectedly, significant portions of pancreas-resident macrophages originated from embryonic development and expanded through in situ proliferation during tumor progression. Whereas monocyte-derived TAMs played more potent roles in antigen presentation, embryonically derived TAMs exhibited a pro-fibrotic transcriptional profile, indicative of their role in producing and remodeling molecules in the extracellular matrix. Collectively, these findings uncover the heterogeneity of TAM origin and functions and could provide therapeutic insight for PDAC treatment.