RESUMEN
Background: Although several approaches have revealed much about individual factors that regulate pancreatic development, we have yet to fully understand their complicated interplay during pancreas morphogenesis. Gfi1 is transcription factor specifically expressed in pancreatic acinar cells, whose role in pancreas cells fate identity and specification is still elusive. Methods: In order to gain further insight into the function of this factor in the pancreas, we generated animals deficient for Gfi1 specifically in the pancreas. Gfi1 conditional knockout animals were phenotypically characterized by immunohistochemistry, RT-qPCR, and RNA scope. To assess the role of Gfi1 in the pathogenesis of diabetes, we challenged Gfi1-deficient mice with two models of induced hyperglycemia: long-term high-fat/high-sugar feeding and streptozotocin injections. Results: Interestingly, mutant mice did not show any obvious deleterious phenotype. However, in depth analyses demonstrated a significant decrease in pancreatic amylase expression, leading to a diminution in intestinal carbohydrates processing and thus glucose absorption. In fact, Gfi1-deficient mice were found resistant to diet-induced hyperglycemia, appearing normoglycemic even after long-term high-fat/high-sugar diet. Another feature observed in mutant acinar cells was the misexpression of ghrelin, a hormone previously suggested to exhibit anti-apoptotic effects on ß-cells in vitro. Impressively, Gfi1 mutant mice were found to be resistant to the cytotoxic and diabetogenic effects of high-dose streptozotocin administrations, displaying a negligible loss of ß-cells and an imperturbable normoglycemia. Conclusions: Together, these results demonstrate that Gfi1 could turn to be extremely valuable for the development of new therapies and could thus open new research avenues in the context of diabetes research.
Asunto(s)
Proteínas de Unión al ADN/deficiencia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/prevención & control , Factores de Transcripción/deficiencia , Células Acinares/citología , Células Acinares/metabolismo , Amilasas/metabolismo , Animales , Diferenciación Celular/genética , Proliferación Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Diabetes Mellitus/genética , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Ghrelina/metabolismo , Proteínas de Homeodominio/metabolismo , Hiperglucemia/complicaciones , Hiperglucemia/genética , Integrasas/metabolismo , Ratones Transgénicos , Mutación/genética , Páncreas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
In the context of type 1 diabetes research and the development of insulin-producing ß-cell replacement strategies, whether pancreatic ductal cells retain their developmental capability to adopt an endocrine cell identity remains debated, most likely due to the diversity of models employed to induce pancreatic regeneration. In this work, rather than injuring the pancreas, we developed a mouse model allowing the inducible misexpression of the proendocrine gene Neurog3 in ductal cells in vivo. These animals developed a progressive islet hypertrophy attributed to a proportional increase in all endocrine cell populations. Lineage tracing experiments indicated a continuous neo-generation of endocrine cells exhibiting a ductal ontogeny. Interestingly, the resulting supplementary ß-like cells were found to be functional. Based on these findings, we suggest that ductal cells could represent a renewable source of new ß-like cells and that strategies aiming at controlling the expression of Neurog3, or of its molecular targets/co-factors, may pave new avenues for the improved treatments of diabetes.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Plasticidad de la Célula/fisiología , Diabetes Mellitus Tipo 1/patología , Células Endocrinas/fisiología , Proteínas del Tejido Nervioso/metabolismo , Conductos Pancreáticos/fisiología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diabetes Mellitus Tipo 1/genética , Modelos Animales de Enfermedad , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Conductos Pancreáticos/citología , RegeneraciónRESUMEN
The recent demonstration that pancreatic α cells can be continuously regenerated and converted into ß-like cells upon ectopic expression of Pax4 opened new avenues of research in the endocrine cell differentiation and diabetes fields. To determine whether such plasticity was also shared by δ cells, we generated and characterized transgenic animals that express Pax4 specifically in somatostatin-expressing cells. We demonstrate that the ectopic expression of Pax4 in δ cells is sufficient to induce their conversion into functional ß-like cells. Importantly, this conversion induces compensatory mechanisms involving the reactivation of endocrine developmental processes that result in dramatic ß-like cell hyperplasia. Importantly, these ß-like cells are functional and can partly reverse the consequences of chemically induced diabetes.
Asunto(s)
Diabetes Mellitus Experimental/genética , Expresión Génica Ectópica , Proteínas de Homeodominio/genética , Células Secretoras de Insulina/metabolismo , Factores de Transcripción Paired Box/genética , Células Secretoras de Somatostatina/metabolismo , Animales , Proliferación Celular , Transdiferenciación Celular/genética , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/terapia , Terapia Genética/métodos , Glucagón/biosíntesis , Glucagón/genética , Proteínas de Homeodominio/metabolismo , Insulina/biosíntesis , Insulina/genética , Células Secretoras de Insulina/citología , Masculino , Ratones , Ratones Transgénicos , Factores de Transcripción Paired Box/metabolismo , Somatostatina/biosíntesis , Somatostatina/genética , Células Secretoras de Somatostatina/citología , EstreptozocinaRESUMEN
Diabetes is a chronic and progressing disease, the number of patients increasing exponentially, especially in industrialized countries. Regenerating lost insulin-producing cells would represent a promising therapeutic alternative for most diabetic patients. To this end, using the mouse as a model, we reported that GABA, a food supplement, could induce insulin-producing beta-like cell neogenesis offering an attractive and innovative approach for diabetes therapeutics.
RESUMEN
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
The embryonic development of the pancreas is orchestrated by a complex and coordinated transcription factor network. Neurogenin3 (Neurog3) initiates the endocrine program by activating the expression of additional transcription factors driving survival, proliferation, maturation and lineage allocation of endocrine precursors. Among the direct targets of Neurog3, Pax4 appears as one of the key regulators of ß-cell specification. Indeed, mice lacking Pax4 die a few days postpartum, as they develop severe hyperglycemia due to the absence of mature pancreatic ß-cells. Pax4 also directly regulates the expression of Arx, a gene that plays a crucial role in α-cell specification. Comparative analysis of Pax4 and Arx mutants, as well as Arx/Pax4 double mutants, showed that islet subtype destiny is mainly directed by cross-repression of the Pax4 and Arx factors. Importantly, the ectopic expression of Pax4 in α-cells was found sufficient to induce their neogenesis and conversion into ß-like cells, not only during development but also in adult rodents. Therefore, differentiated endocrine α-cells can be considered as a putative source for insulin-producing ß-like cells. These findings have clearly widened our understanding regarding pancreatic development, but they also open new research avenues in the context of diabetes research.