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Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling...
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Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 18946

Special Issue Editor

Prof. Dr. Zhongde Wang

E-Mail Website
Guest Editor
Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322, USA
Interests: genome engineering; transgenics; animal models; epigenetics; stem cells

Special Issue Information

Dear Colleagues,

Animal models play critical roles in the study of human diseases, from identifying the causes of diseases and understanding the pathogenesis of diseases, to the development and testing of drugs or vaccines. It is quite often the case that genetically engineered animal models are needed for these applications, such as for studying the genetics of a disease or in the investigation of the roles of particular genes in the development of a disease. Traditionally, murine species, the laboratory mouse and rat, have been the dominant animal species in human disease modeling, largely due to the fact that embryonic stem cell (ES)-mediated genetic engineering techniques have been available to use for these species and that reagents and many inbred strains of animals have also been available. While mice and rats have been playing essential roles in studying many human diseases, due to the differences between them and humans in genetics and physiology, there are intrinsic limitations in using murine species to study certain aspects of human diseases, and in many instances, they are less suitable than other animal species as human disease models. With the development of new genetic engineering techniques, such as CRISPR/Cas-mediated genome engineering, and assisted reproduction techniques (ART), such as animal cloning by somatic cell nuclear transfer (SCNT), genetic engineering in many non-murine species without the need for ES cells has been made possible and a fast growing list of genetically engineered non-murine animal models, ranging from rodents (e.g., golden Syrian hamsters, guinea pigs, ferrets and rabbits) to farm animals (e.g., ,pigs, goats, sheep and cattle), has been developed and is filling in the gaps where studies with murine models are unsuitable.

In this Special Issue, we invite leading experts in the field to provide a comprehensive update on the latest development and applications of genetically engineered non-murine animal models.

Prof. Dr. Zhongde Wang
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • animal models
  • genetic engineering
  • transgenic
  • human disease modeling
  • CRISPR/Cas
  • assisted reproduction technology

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Published Papers (5 papers)

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Research

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15 pages, 4672 KiB  
Article
DAZL Knockout Pigs as Recipients for Spermatogonial Stem Cell Transplantation
by Nathalia L. M. Lara, Taylor Goldsmith, Paula Rodriguez-Villamil, Felipe Ongaratto, Staci Solin, Dennis Webster, Uyanga Ganbaatar, Shane Hodgson, Stanislas M. A. S. Corbière, Alla Bondareva, Daniel F. Carlson and Ina Dobrinski
Cells 2023, 12(21), 2582; https://doi.org/10.3390/cells12212582 - 6 Nov 2023
Cited by 1 | Viewed by 2063
Abstract
Spermatogonial stem cell (SSC) transplantation into the testis of a germ cell (GC)-depleted surrogate allows transmission of donor genotype via donor-derived sperm produced by the recipient. Transplantation of gene-edited SSCs provides an approach to propagate gene-edited large animal models. DAZL is a conserved [...] Read more.
Spermatogonial stem cell (SSC) transplantation into the testis of a germ cell (GC)-depleted surrogate allows transmission of donor genotype via donor-derived sperm produced by the recipient. Transplantation of gene-edited SSCs provides an approach to propagate gene-edited large animal models. DAZL is a conserved RNA-binding protein important for GC development, and DAZL knockout (KO) causes defects in GC commitment and differentiation. We characterized DAZL-KO pigs as SSC transplantation recipients. While there were GCs in 1-week-old (wko) KO, complete GC depletion was observed by 10 wko. Donor GCs were transplanted into 18 DAZL-KO recipients at 10–13 wko. At sexual maturity, semen and testes were evaluated for transplantation efficiency and spermatogenesis. Approximately 22% of recipient seminiferous tubules contained GCs, including elongated spermatids and proliferating spermatogonia. The ejaculate of 89% of recipients contained sperm, exclusively from donor origin. However, sperm concentration was lower than the wild-type range. Testicular protein expression and serum hormonal levels were comparable between DAZL-KO and wild-type. Intratesticular testosterone and Leydig cell volume were increased, and Leydig cell number decreased in transplanted DAZL-KO testis compared to wild-type. In summary, DAZL-KO pigs support donor-derived spermatogenesis following SSC transplantation, but low spermatogenic efficiency currently limits their use for the production of offspring. Full article
(This article belongs to the Special Issue Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications)
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15 pages, 2700 KiB  
Article
Improving the Efficiency of Precise Genome Editing with CRISPR/Cas9 to Generate Goats Overexpressing Human Butyrylcholinesterase
by Jia-Hao Wang, Su-Jun Wu, Yan Li, Yue Zhao, Zhi-Mei Liu, Shou-Long Deng and Zheng-Xing Lian
Cells 2023, 12(14), 1818; https://doi.org/10.3390/cells12141818 - 10 Jul 2023
Cited by 3 | Viewed by 2525
Abstract
The CRISPR/Cas9 system is widely used for genome editing in livestock production, although off-target effects can occur. It is the main method to produce genome-edited goats by somatic cell nuclear transfer (SCNT) of CRISPR/Cas9-mediated genome-edited primary goat fetal fibroblast cells (GFFs). Improving the [...] Read more.
The CRISPR/Cas9 system is widely used for genome editing in livestock production, although off-target effects can occur. It is the main method to produce genome-edited goats by somatic cell nuclear transfer (SCNT) of CRISPR/Cas9-mediated genome-edited primary goat fetal fibroblast cells (GFFs). Improving the double-strand break (DSB) efficiency of Cas9 in primary cells would improve the homologous repair (HR) efficiency. The low efficiency of HR remains a major hurdle in CRISPR/Cas9-mediated precise genome editing, increasing the work required to screen the genome-edited primary cell clones. In this study, we modified several essential parameters that affect the efficiency of the CRISPR/Cas9-mediated knock-in GFF cloning system, including establishing a high-efficiency transfection system for primary cells via nucleofection and optimizing homology arm (HA) length during HR. Here, we specifically inserted a recombinant human butyrylcholinesterase gene (rhBChE) into the goat fibroblast growth factor (FGF)-5 locus through the CRISPR/Cas9 system, thereby achieving simultaneous rhBChE insertion and FGF5 knock-out. First, this study introduced the Cas9, FGF5 knock-out small guide RNA, and rhBChE knock-in donors into GFFs by electroporation and obtained positive cell clones without off-target effects. Then, we demonstrated the expression of rhBChE in GFF clones and verified its function. Finally, we obtained a CRISPR/Cas9-mediated rhBChE-overexpression goat. Full article
(This article belongs to the Special Issue Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications)
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20 pages, 4600 KiB  
Article
Genetically Engineered Pigs as Efficient Salivary Gland Bioreactors for Production of Therapeutically Valuable Human Nerve Growth Factor
by Fang Zeng, Sha Liao, Zhe Kuang, Qingchun Zhu, Hengxi Wei, Junsong Shi, Enqin Zheng, Zheng Xu, Sixiu Huang, Linjun Hong, Ting Gu, Jie Yang, Huaqiang Yang, Gengyuan Cai, Stefan Moisyadi, Johann Urschitz, Zicong Li and Zhenfang Wu
Cells 2022, 11(15), 2378; https://doi.org/10.3390/cells11152378 - 2 Aug 2022
Cited by 4 | Viewed by 3765
Abstract
Farm animal salivary glands hold great potential as efficient bioreactors for production of human therapeutic proteins. Nerve growth factor (NGF) is naturally expressed in animal salivary glands and has been approved for human clinical treatment. This study aims to employ transgenic (TG) pig [...] Read more.
Farm animal salivary glands hold great potential as efficient bioreactors for production of human therapeutic proteins. Nerve growth factor (NGF) is naturally expressed in animal salivary glands and has been approved for human clinical treatment. This study aims to employ transgenic (TG) pig salivary gland as bioreactors for efficient synthesis of human NGF (hNGF). hNGF-TG pigs were generated by cloning in combination with piggyBac transposon-mediated gene transfer. These hNGF-TG pigs specifically expressed hNGF protein in their salivary glands and secreted it at high levels into saliva. Surgical and nonsurgical approaches were developed to efficiently collect saliva from hNGF-TG pigs. hNGF protein was successfully purified from collected saliva and was verified to be biologically active. In an additional step, the double-transgenic pigs, where the endogenous porcine NGF (pNGF) gene was replaced by another copy of hNGF transgene, were created by cloning combined with CRISPR/Cas9-mediated homologous recombination. These double-transgenic pigs expressed hNGF but not pNGF, thus avoiding possible “contamination” of hNGF with pNGF protein during purification. In conclusion, TG pig salivary glands can be used as robust bioreactors for a large-scale synthesis of functional hNGF or other valuable proteins. This new animal pharming method will benefit both human health and biomedicine. Full article
(This article belongs to the Special Issue Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications)
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Review

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27 pages, 2233 KiB  
Review
Modelling Neurological Diseases in Large Animals: Criteria for Model Selection and Clinical Assessment
by Samantha L. Eaton, Fraser Murdoch, Nina M. Rzechorzek, Gerard Thompson, Claudia Hartley, Benjamin Thomas Blacklock, Chris Proudfoot, Simon G. Lillico, Peter Tennant, Adrian Ritchie, James Nixon, Paul M. Brennan, Stefano Guido, Nadia L. Mitchell, David N. Palmer, C. Bruce A. Whitelaw, Jonathan D. Cooper and Thomas M. Wishart
Cells 2022, 11(17), 2641; https://doi.org/10.3390/cells11172641 - 25 Aug 2022
Cited by 3 | Viewed by 4471
Abstract
Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high [...] Read more.
Issue: The impact of neurological disorders is recognised globally, with one in six people affected in their lifetime and few treatments to slow or halt disease progression. This is due in part to the increasing ageing population, and is confounded by the high failure rate of translation from rodent-derived therapeutics to clinically effective human neurological interventions. Improved translation is demonstrated using higher order mammals with more complex/comparable neuroanatomy. These animals effectually span this translational disparity and increase confidence in factors including routes of administration/dosing and ability to scale, such that potential therapeutics will have successful outcomes when moving to patients. Coupled with advancements in genetic engineering to produce genetically tailored models, livestock are increasingly being used to bridge this translational gap. Approach: In order to aid in standardising characterisation of such models, we provide comprehensive neurological assessment protocols designed to inform on neuroanatomical dysfunction and/or lesion(s) for large animal species. We also describe the applicability of these exams in different large animals to help provide a better understanding of the practicalities of cross species neurological disease modelling. Recommendation: We would encourage the use of these assessments as a reference framework to help standardise neurological clinical scoring of large animal models. Full article
(This article belongs to the Special Issue Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications)
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16 pages, 1812 KiB  
Review
Golden Syrian Hamster Models for Cancer Research
by Zhongde Wang and Robert T. Cormier
Cells 2022, 11(15), 2395; https://doi.org/10.3390/cells11152395 - 3 Aug 2022
Cited by 14 | Viewed by 5058
Abstract
The golden Syrian hamster (Mesocricetus auratus) has long been a valuable rodent model of human diseases, especially infectious and metabolic diseases. Hamsters have also been valuable models of several chemically induced cancers such as the DMBA-induced oral cheek pouch cancer model. [...] Read more.
The golden Syrian hamster (Mesocricetus auratus) has long been a valuable rodent model of human diseases, especially infectious and metabolic diseases. Hamsters have also been valuable models of several chemically induced cancers such as the DMBA-induced oral cheek pouch cancer model. Recently, with the application of CRISPR/Cas9 genetic engineering technology, hamsters can now be gene targeted as readily as mouse models. This review describes the phenotypes of three gene-targeted knockout (KO) hamster cancer models, TP53, KCNQ1, and IL2RG. Notably, these hamster models demonstrate cancer phenotypes not observed in mouse KOs. In some cases, the cancers that arise in the KO hamster are similar to cancers that arise in humans, in contrast with KO mice that do not develop the cancers. An example is the development of aggressive acute myelogenous leukemia (AML) in TP53 KO hamsters. The review also presents a discussion of the relative strengths and weaknesses of mouse cancer models and hamster cancer models and argues that there are no perfect rodent models of cancer and that the genetically engineered hamster cancer models can complement mouse models and expand the suite of animal cancer models available for the development of new cancer therapies. Full article
(This article belongs to the Special Issue Advances in Genetic Engineered Non-murine Mammalian Species – Human Disease Modeling and Other Biomedical Applications)
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