Pancreas phylogeny and ontogeny in relation to a ‘pancreatic stem cell’

Blood glucose regulation has likely evolved during early vertebrate evolution to allow and secure the concurrent evolution of complex brains and nervous systems: “an inner milieu of constant blood glucose levels through millions of years has provided an extra degree of freedom for the brain to evolve without having to think of getting energy supply”. Key regulators of blood-glucose, insulin & glucagon, are produced by the dominating cell types of the pancreatic Islet of Langerhans: the insulin producing beta-cell and the glucagon producing alpha-cell. Interestingly, it appears that the beta cell pioneered the formation or the foundation of the pancreatic organ according to current phylogenetic insights. Such phylogenetic aspects of a pancreatic stem cell are at the end discussed in relation to directed differentiation of ES-cells towards therapeutic beta-cells

Insulin gene regulation and islet development as studied in genetically modified tumors and transgenic laboratory animals

The pancreatic islet of Langerhans is composed of four highly distinct cell types specialized to mass produce a particular hormone. Insulin is thus the main product released from the islet B—cell in response to elevated glucose.The four cell types maturate during fetal development. Pluripotent rat islet tumors can to a certain degree undergo similar maturation processes when passaged in vivo. Such a model has been used to study the B—cell specific process of insulin gene activation. Transgenic mice have been instrumental in defining the functional regulatory elements involved in restricting the insulin gene activity to the pancreatic B-cell. The tissue-specific enhancer/promoter has thus been identified and used in combination with a series of other genes which in transgenic mice targets expression of the gene in question selectively to the B-cell. Important transacting factors have been identified and cloned which are in part responsible for mediating tissue specific insulin gene expression. One such factor when "knocked-out" results in a phenotype lacking the entire pancreas. Future developments in targeting "knockout" of genes to particular cell types will help dissecting out the multiple functions of such regulatory transacting factors

Organoids: a promising new in vitro platform in livestock and veterinary research.

Organoids are self-organizing, self-renewing three-dimensional cellular structures that resemble organs in structure and function. They can be derived from adult stem cells, embryonic stem cells, or induced pluripotent stem cells. They contain most of the relevant cell types with a topology and cell-to-cell interactions resembling that of the in vivo tissue. The widespread and increasing adoption of organoid-based technologies in human biomedical research is testament to their enormous potential in basic, translational- and applied-research. In a similar fashion there appear to be ample possibilities for research applications of organoids from livestock and companion animals. Furthermore, organoids as in vitro models offer a great possibility to reduce the use of experimental animals. Here, we provide an overview of studies on organoids in livestock and companion animal species, with focus on the methods developed for organoids from a variety of tissues/organs from various animal species and on the applications in veterinary research. Current limitations, and ongoing research to address these limitations, are discussed. Further, we elaborate on a number of fields of research in animal nutrition, host-microbe interactions, animal breeding and genomics, and animal biotechnology, in which organoids may have great potential as an in vitro research tool

Deregressed EBV as the response variable yield more reliable genomic predictions than traditional EBV in pure-bred pigs

<p>Abstract</p> <p>Background</p> <p>Genomic selection can be implemented by a multi-step procedure, which requires a response variable and a statistical method. For pure-bred pigs, it was hypothesised that deregressed estimated breeding values (EBV) with the parent average removed as the response variable generate higher reliabilities of genomic breeding values than EBV, and that the normal, thick-tailed and mixture-distribution models yield similar reliabilities.</p> <p>Methods</p> <p>Reliabilities of genomic breeding values were estimated with EBV and deregressed EBV as response variables and under the three statistical methods, genomic BLUP, Bayesian Lasso and MIXTURE. The methods were examined by splitting data into a reference data set of 1375 genotyped animals that were performance tested before October 2008, and 536 genotyped validation animals that were performance tested after October 2008. The traits examined were daily gain and feed conversion ratio.</p> <p>Results</p> <p>Using deregressed EBV as the response variable yielded 18 to 39% higher reliabilities of the genomic breeding values than using EBV as the response variable. For daily gain, the increase in reliability due to deregression was significant and approximately 35%, whereas for feed conversion ratio it ranged between 18 and 39% and was significant only when MIXTURE was used. Genomic BLUP, Bayesian Lasso and MIXTURE had similar reliabilities.</p> <p>Conclusions</p> <p>Deregressed EBV is the preferred response variable, whereas the choice of statistical method is less critical for pure-bred pigs. The increase of 18 to 39% in reliability is worthwhile, since the reliabilities of the genomic breeding values directly affect the returns from genomic selection.</p

YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration.

Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element.This work was supported by Worldwide Cancer Research (13-1216 to KBJ), Lundbeck Foundation (R105-A9755 to KBJ), the Danish Cancer Society (R56-A2907 and R124-A7724 to KBJ), the Carlsberg Foundation (to KBJ), EMBO Young Investigator programme (to KBJ), AIRC Special Program Molecular Clinical Oncology ‘‘5 per mille’’ (to SP), an AIRC PI-Grant (to SP), Epigenetics Flagship projects (CNR-Miur grants. to SP), the DFF mobilix programme (to SY), Marie Curie fellowship programme (SY and JG), Foundation of Aase and Ejnar Danielsen (OHN), Axel Muusfeldts Foundation (OHN), The Ragnar Söderberg Foundation (CDM). This project has received funding from the European Union’s Horizon 2020 research and innovation programme (grant agreements STEMHEALTH ERCCoG682665 and INTENS 668294 to KBJ and DENOVOSTEM No. 670126 to SP)

Calprotectin — A Novel Marker of Obesity

BACKGROUND: The two inflammatory molecules, S100A8 and S100A9, form a heterodimer, calprotectin. Plasma calprotectin levels are elevated in various inflammatory disorders. We hypothesized that plasma calprotectin levels would be increased in subjects with low-grade systemic inflammation i.e. either obese subjects or subjects with type 2 diabetes. METHODOLOGY/PRINCIPAL FINDINGS: Plasma calprotectin and skeletal muscle S100A8 mRNA levels were measured in a cohort consisting of 199 subjects divided into four groups depending on presence or absence of type 2 diabetes (T2D), and presence or absence of obesity. There was a significant interaction between obesity and T2D (p = 0.012). Plasma calprotectin was increased in obese relative to non-obese controls (p<0.0001), whereas it did not differ between obese and non-obese patients with T2D (p = 0.62). S100A8 mRNA levels in skeletal muscle were not influenced by obesity or T2D. Multivariate regression analysis (adjusting for age, sex, smoking and HOMA2-IR) showed plasma calprotectin to be strongly associated with BMI, even when further adjusted for fitness, CRP, TNF-alpha or neutrophil number. CONCLUSIONS/SIGNIFICANCE: Plasma calprotectin is a marker of obesity in individuals without type 2 diabetes

YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration

Tissue regeneration requires dynamic cellular adaptation to the wound environment. It is currently unclear how this is orchestrated at the cellular level and how cell fate is affected by severe tissue damage. Here we dissect cell fate transitions during colonic regeneration in a mouse dextran sulfate sodium (DSS) colitis model, and we demonstrate that the epithelium is transiently reprogrammed into a primitive state. This is characterized by de novo expression of fetal markers as well as suppression of markers for adult stem and differentiated cells. The fate change is orchestrated by remodeling the extracellular matrix (ECM), increased FAK/Src signaling, and ultimately YAP/TAZ activation. In a defined cell culture system recapitulating the extracellular matrix remodeling observed in vivo, we show that a collagen 3D matrix supplemented with Wnt ligands is sufficient to sustain endogenous YAP/TAZ and induce conversion of cell fate. This provides a simple model for tissue regeneration, implicating cellular reprogramming as an essential element