Genetically engineered pigs as models for human disease

Perleberg, Carolin; Kind, Alexander; Schnieke, Angelika

doi:10.1242/dmm.030783

Cited by 177 publications

(146 citation statements)

References 177 publications

(210 reference statements)

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“…Modelling polyposis and CRC in pigs offers a useful additional resource to mouse models to study the pathobiology of polyposis and CRC (Perleberg et al 2018). The APC 1311/+ pig allows human scale procedures such as endoscopic monitoring and polyp biopsy, and enables comparative analyses that are not possible in human populations.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

et al. 2018

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Familial adenomatous polyposis (FAP) is a hereditary predisposition to formation of colon polyps that can progress to colorectal cancer (CRC). The severity of polyposis varies substantially within families bearing the same germline mutation in the adenomatous polyposis coli (APC) tumour suppressor gene. The progressive step-wise accumulation of genetic events in tumour suppressor genes and oncogenes leads to oncogenic transformation, with driver alterations in the tumour protein p53 (TP53) gene playing a key role in advanced stage CRC. We analysed groups of pigs carrying a truncating mutation in APC (APC; orthologous to human APC) to study the influence of TP53 polymorphisms and expression on the frequency of polyp formation and polyp progression in early-stage FAP. Five generations of APC pigs were examined by colonoscopy for polyposis severity and development. A total of 19 polymorphisms were found in 5'-flanking, coding, and 3' untranslated regions of TP53. The distribution of TP53 genotypes did not differ between APC pigs with low (LP) and high (HP) number of colon polyps. p53 mRNA expression was analysed in distally located normal mucosa samples of wild-type pigs, APC LP and HP pigs, and also in distally located polyp samples histologically classified as low-grade (LG-IEN) and high-grade intraepithelial dysplastic (HG-IEN) from APC pigs. p53 mRNA expression was found to be significantly elevated in HG-IEN compared to LG-IEN samples (p = 0.012), suggesting a role for p53 in the early precancerous stages of polyp development.

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Section: Discussionmentioning

confidence: 99%

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

et al. 2018

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“…Humans are evolutionary closer to swine than rodents, and thus genetic differences are~30% less prevalent between porcine models and patients [31]. While genetic manipulation of these porcine models is generally more arduous than murine models, recently developed genetic tools (most notably CRISPR/Cas9) have made precise modifications feasible [32]. Regardless, mice and other rodents will remain the primary experimental VTE model for the conceivable future, as they are less expensive principally due to their small size.…”

Section: Dependence On Murine Modelsmentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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“…Pigs are increasingly used as a dual-purpose model in agriculture and biomedical research [1][2][3]. The production of in vitro produced (IVP) embryos is an essential step involved in the generation of pigs for research.…”

Section: Introductionmentioning

confidence: 99%

Maternal Yes-Associated Protein Participates in Porcine Blastocyst Development via Modulation of Trophectoderm Epithelium Barrier Function

Cao

et al. 2019

Cells

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The establishment of a functional trophectoderm (TE) epithelium is an essential prerequisite for blastocyst formation and placentation. Transcription coactivator yes-associated protein (YAP), a downstream effector of the hippo signaling pathway, is required for specification of both the TE and epiblast lineages in mice. However, the biological role of YAP in porcine blastocyst development is not known. Here, we report that maternally derived YAP protein is localized to both the cytoplasm and nuclei prior to the morula stage and is then predominantly localized to the TE nuclei in blastocysts. Functionally, maternal YAP knockdown severely impeded blastocyst formation and perturbed the allocation of the first two lineages. The treatment of embryos with verteporfin, a pharmacological inhibitor of YAP, faithfully recapitulated the phenotype observed in YAP deleted embryos. Mechanistically, we found that maternal YAP regulates multiple genes which are important for lineage commitment, tight junction assembly, and fluid accumulation. Consistent with the effects on tight junction gene expression, a permeability assay revealed that paracellular sealing was defective in the trophectoderm epithelium. Lastly, YAP knockdown in a single blastomere at the 2-cell stage revealed that the cellular progeny of the YAP + blastomere were sufficient to sustain blastocyst formation via direct complementation of the defective trophectoderm epithelium. In summary, these findings demonstrate that maternal YAP facilitates porcine blastocyst development through transcriptional regulation of key genes that are essential for lineage commitment, tight junction assembly, and fluid accumulation.

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Genetically engineered pigs as models for human disease

Cited by 177 publications

References 177 publications

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

Elevated expression of p53 in early colon polyps in a pig model of human familial adenomatous polyposis

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Maternal Yes-Associated Protein Participates in Porcine Blastocyst Development via Modulation of Trophectoderm Epithelium Barrier Function

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