Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/41667 |
Resumo: | Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). |
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Orge, Iasmim DinizGadd, Victoria LBarouh, Judah LeãoRossi, Erik AranhaCarvalho, Rejane HughesSmith, IanAllahdadi, Kyan JamesParedes, Bruno DiazSilva, Daniela NascimentoDamasceno, Patrícia Kauanna FSampaio, Gabriela LouiseForbes, Stuart JSoares, Milena Botelho PereiraSouza, Bruno Solano de Freitas2020-06-16T13:11:07Z2020-06-16T13:11:07Z2020ORGE, Iasmim Diniz et al. instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells. Stem Cell Research & Therapy, v. 11, p. 154, 2020.1757-6512https://www.arca.fiocruz.br/handle/icict/4166710.1186/s13287-020-01665-zFundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil.MRC Centre for Regenerative Medicine. Edinburgh, UK.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil / Institute for Research and Education. Rio de Janeiro, RJ, Brazil.Federal U niversity of Bahia. Institute of Health Sciences. Salvador, BA, Brazil.MRC Centre for Regenerative Medicine. Edinburgh, UK.São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil / Institute for Research and Education. Rio de Janeiro, RJ, Brazil.São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil / Institute for Research and Education. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil.MRC Centre for Regenerative Medicine. Edinburgh, UK.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil.Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / São Rafael Hospital.Center for Biotechnology and Cell Therapy. Salvador, BA, Brazil / Institute for Research and Education. Rio de Janeiro, RJ, Brazil / National Institute of Science and Technology for Regenerative Medicine. Rio de Janeiro, RJ, Brazil /Hepatocyte-like cells (iHEPs) generated by transcription factor-mediated direct reprogramming of somatic cells have been studied as potential cell sources for the development of novel therapies targeting liver diseases. The mechanisms involved in direct reprogramming, stability after long-term in vitro expansion, and safety profile of reprogrammed cells in different experimental models, however, still require further investigation. Methods: iHEPs were generated by forced expression of Foxa2/Hnf4a in mouse mesenchymal stromal cells and characterized their phenotype stability by in vitro and in vivo analyses. Results: The iHEPs expressed mixed hepatocyte and liver progenitor cell markers, were highly proliferative, and presented metabolic activities in functional assays. A progressive loss of hepatic phenotype, however, was observed after several passages, leading to an increase in alpha-SMA+ fibroblast-like cells, which could be distinguished and sorted from iHEPs by differential mitochondrial content. The resulting purified iHEPs proliferated, maintained liver progenitor cell markers, and, upon stimulation with lineage maturation media, increased expression of either biliary or hepatocyte markers. In vivo functionality was assessed in independent pre-clinical mouse models. Minimal engraftment was observed following transplantation in mice with acute acetaminophen-induced liver injury. In contrast, upon transplantation in a transgenic mouse model presenting host hepatocyte senescence, widespread engraftment and uncontrolled proliferation of iHEPs was observed, forming islands of epithelial-like cells, adipocytelike cells, or cells presenting both morphologies. Conclusion: The results have significant implications for cell reprogramming, suggesting that iHEPs generated by Foxa2/Hnf4a expression have an unstable phenotype and depend on transgene expression for maintenance of hepatocyte-like characteristics, showing a tendency to return to the mesenchymal phenotype of origin and a compromised safety profile.engBMCHepatócitosReprogramação celularCélulas estromais mesenquimaisHepatocyte-like cells,Direct reprogramming,Mesenchymal stromal cellsPhenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cellsinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/41667/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALAlmeida.S.R. GC-MS Profile....pdfAlmeida.S.R. GC-MS Profile....pdfapplication/pdf16688520https://www.arca.fiocruz.br/bitstream/icict/41667/2/Almeida.S.R.%20GC-MS%20Profile....pdf81805a4fb0f95e25e504b56cdf48b797MD52TEXTAlmeida.S.R. GC-MS Profile....pdf.txtAlmeida.S.R. 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| dc.title.pt_BR.fl_str_mv |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| title |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| spellingShingle |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells Orge, Iasmim Diniz Hepatócitos Reprogramação celular Células estromais mesenquimais Hepatocyte-like cells, Direct reprogramming, Mesenchymal stromal cells |
| title_short |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| title_full |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| title_fullStr |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| title_full_unstemmed |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| title_sort |
Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells |
| author |
Orge, Iasmim Diniz |
| author_facet |
Orge, Iasmim Diniz Gadd, Victoria L Barouh, Judah Leão Rossi, Erik Aranha Carvalho, Rejane Hughes Smith, Ian Allahdadi, Kyan James Paredes, Bruno Diaz Silva, Daniela Nascimento Damasceno, Patrícia Kauanna F Sampaio, Gabriela Louise Forbes, Stuart J Soares, Milena Botelho Pereira Souza, Bruno Solano de Freitas |
| author_role |
author |
| author2 |
Gadd, Victoria L Barouh, Judah Leão Rossi, Erik Aranha Carvalho, Rejane Hughes Smith, Ian Allahdadi, Kyan James Paredes, Bruno Diaz Silva, Daniela Nascimento Damasceno, Patrícia Kauanna F Sampaio, Gabriela Louise Forbes, Stuart J Soares, Milena Botelho Pereira Souza, Bruno Solano de Freitas |
| author2_role |
author author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Orge, Iasmim Diniz Gadd, Victoria L Barouh, Judah Leão Rossi, Erik Aranha Carvalho, Rejane Hughes Smith, Ian Allahdadi, Kyan James Paredes, Bruno Diaz Silva, Daniela Nascimento Damasceno, Patrícia Kauanna F Sampaio, Gabriela Louise Forbes, Stuart J Soares, Milena Botelho Pereira Souza, Bruno Solano de Freitas |
| dc.subject.other.pt_BR.fl_str_mv |
Hepatócitos Reprogramação celular Células estromais mesenquimais |
| topic |
Hepatócitos Reprogramação celular Células estromais mesenquimais Hepatocyte-like cells, Direct reprogramming, Mesenchymal stromal cells |
| dc.subject.en.pt_BR.fl_str_mv |
Hepatocyte-like cells, Direct reprogramming, Mesenchymal stromal cells |
| description |
Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). |
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2020 |
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2020-06-16T13:11:07Z |
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2020-06-16T13:11:07Z |
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2020 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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ORGE, Iasmim Diniz et al. instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells. Stem Cell Research & Therapy, v. 11, p. 154, 2020. |
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https://www.arca.fiocruz.br/handle/icict/41667 |
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1757-6512 |
| dc.identifier.doi.none.fl_str_mv |
10.1186/s13287-020-01665-z |
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ORGE, Iasmim Diniz et al. instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells. Stem Cell Research & Therapy, v. 11, p. 154, 2020. 1757-6512 10.1186/s13287-020-01665-z |
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https://www.arca.fiocruz.br/handle/icict/41667 |
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eng |
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