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      Generation of induced pluripotent stem cells from large domestic animals


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          Induced pluripotent stem cells (iPSCs) have enormous potential in developmental biology studies and in cellular therapies. Although extensively studied and characterized in human and murine models, iPSCs from animals other than mice lack reproducible results.


          Herein, we describe the generation of robust iPSCs from equine and bovine cells through lentiviral transduction of murine or human transcription factors Oct4, Sox2, Klf4, and c-Myc and from human and murine cells using similar protocols, even when different supplementations were used. The iPSCs were analyzed regarding morphology, gene and protein expression of pluripotency factors, alkaline phosphatase detection, and spontaneous and induced differentiation.


          Although embryonic-derived stem cells are yet not well characterized in domestic animals, generation of iPS cells from these species is possible through similar protocols used for mouse or human cells, enabling the use of pluripotent cells from large animals for basic or applied purposes. Herein, we also infer that bovine iPS (biPSCs) exhibit similarity to mouse iPSCs (miPSCs), whereas equine iPSs (eiPSCs) to human (hiPSCs).


          The generation of reproducible protocols in different animal species will provide an informative tool for producing in vitro autologous pluripotent cells from domestic animals. These cells will create new opportunities in animal breeding through transgenic technology and will support a new era of translational medicine with large animal models.

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          Most cited references23

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          In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state.

          Nuclear transplantation can reprogramme a somatic genome back into an embryonic epigenetic state, and the reprogrammed nucleus can create a cloned animal or produce pluripotent embryonic stem cells. One potential use of the nuclear cloning approach is the derivation of 'customized' embryonic stem (ES) cells for patient-specific cell treatment, but technical and ethical considerations impede the therapeutic application of this technology. Reprogramming of fibroblasts to a pluripotent state can be induced in vitro through ectopic expression of the four transcription factors Oct4 (also called Oct3/4 or Pou5f1), Sox2, c-Myc and Klf4. Here we show that DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells. Notably, the cells-derived from mouse fibroblasts-can form viable chimaeras, can contribute to the germ line and can generate live late-term embryos when injected into tetraploid blastocysts. Our results show that the biological potency and epigenetic state of in-vitro-reprogrammed induced pluripotent stem cells are indistinguishable from those of ES cells.
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            Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds.

            Reprogramming of mouse and human somatic cells can be achieved by ectopic expression of transcription factors, but with low efficiencies. We report that DNA methyltransferase and histone deacetylase (HDAC) inhibitors improve reprogramming efficiency. In particular, valproic acid (VPA), an HDAC inhibitor, improves reprogramming efficiency by more than 100-fold, using Oct4-GFP as a reporter. VPA also enables efficient induction of pluripotent stem cells without introduction of the oncogene c-Myc.
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              Structure and evolution of transcriptional regulatory networks.

              The regulatory interactions between transcription factors and their target genes can be conceptualised as a directed graph. At a global level, these regulatory networks display a scale-free topology, indicating the presence of regulatory hubs. At a local level, substructures such as motifs and modules can be discerned in these networks. Despite the general organisational similarity of networks across the phylogenetic spectrum, there are interesting qualitative differences among the network components, such as the transcription factors. Although the DNA-binding domains of the transcription factors encoded by a given organism are drawn from a small set of ancient conserved superfamilies, their relative abundance often shows dramatic variation among different phylogenetic groups. Large portions of these networks appear to have evolved through extensive duplication of transcription factors and targets, often with inheritance of regulatory interactions from the ancestral gene. Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms.

                Author and article information

                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                25 June 2020
                25 June 2020
                : 11
                [1 ]GRID grid.11899.38, ISNI 0000 0004 1937 0722, Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, , University of São Paulo, ; Pirassununga, Brazil
                [2 ]GRID grid.11899.38, ISNI 0000 0004 1937 0722, Postgraduate Program in Anatomy of Domestic and Wild Animals, School of Veterinary Medicine and Animal Science, , University of São Paulo, ; São Paulo, Brazil
                [3 ]GRID grid.11899.38, ISNI 0000 0004 1937 0722, Center for Cell-Based Therapy, Regional Blood Center, School of Medicine of Ribeirão Preto, , University of São Paulo, ; Ribeirão Preto, Brazil
                [4 ]GRID grid.11899.38, ISNI 0000 0004 1937 0722, Heart Institute (INCOR), Faculty of Medicine, , University of São Paulo, ; São Paulo, Brazil
                [5 ]GRID grid.38142.3c, ISNI 000000041936754X, Present Address: Brigham and Women’s Hospital, , Harvard Medical School, ; Boston, USA
                [6 ]GRID grid.5386.8, ISNI 000000041936877X, Present Address: Weill Cornell Medicine, , Cornell University, ; Ithaca, USA
                [7 ]GRID grid.11899.38, ISNI 0000 0004 1937 0722, School of Pharmaceutical Sciences of Ribeirão Preto, , University of São Paulo, ; Ribeirão Preto, SP Brazil
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funded by: FundRef http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: 2009/11631-6
                Award ID: 2011/08376-4
                Award ID: 2013/13686-8
                Award ID: 2013/08135-2
                Award ID: 2015/26818-5
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002322, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior;
                Award ID: 001
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;
                Award ID: 82163/2013-5
                Award Recipient :
                Custom metadata
                © The Author(s) 2020

                Molecular medicine
                bovine,cellular reprogramming,equine,induced pluripotency,ipscs,stem cells
                Molecular medicine
                bovine, cellular reprogramming, equine, induced pluripotency, ipscs, stem cells


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