Phenotype instability of hepatocyte-like cells produced by direct reprogramming of mesenchymal stromal cells

Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Bibliographic Details
Authors: 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
Format: article
Status:Published version
Publication Date:2020
Country:Brasil
Institution:Fundação Oswaldo Cruz (FIOCRUZ)
Repository:Repositório Institucional da FIOCRUZ (ARCA)
Language:English
OAI Identifier:oai:arca.fiocruz.br:icict/41319
Online Access:https://arca.fiocruz.br/handle/icict/41319
Access Level:Open access
Keyword:Células hepatócitos
Reprogramação celular
Células Mesenquimais Estromais
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dc.title.none.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
Células hepatócitos
Reprogramação celular
Células Mesenquimais Estromais
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
dc.creator.none.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
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.subject.other.none.fl_str_mv Células hepatócitos
Reprogramação celular
Células Mesenquimais Estromais
topic Células hepatócitos
Reprogramação celular
Células Mesenquimais Estromais
description Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
publishDate 2020
dc.date.accessioned.fl_str_mv 2020-05-20T14:09:16Z
dc.date.available.fl_str_mv 2020-05-20T14:09:16Z
dc.date.issued.fl_str_mv 2020
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv 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.
dc.identifier.uri.fl_str_mv https://arca.fiocruz.br/handle/icict/41319
dc.identifier.issn.none.fl_str_mv 1757-6512
dc.identifier.doi.none.fl_str_mv 10.1186/s13287-020-01665-z
identifier_str_mv 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
url https://arca.fiocruz.br/handle/icict/41319
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
instacron:FIOCRUZ
instname_str Fundação Oswaldo Cruz (FIOCRUZ)
instacron_str FIOCRUZ
institution FIOCRUZ
reponame_str Repositório Institucional da FIOCRUZ (ARCA)
collection Repositório Institucional da FIOCRUZ (ARCA)
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spelling 2020-05-20T14:09:16Z2020-05-20T14:09:16Z2020ORGE, 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://arca.fiocruz.br/handle/icict/4131910.1186/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 / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil.Universidade Federal da Bahia. Institute of Health Sciences. Salvador, BA, Brasil.MRC Centre for Regenerative Medicine. Edinburgh, UK.São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil.São Rafael Hospital. Center for Biotechnology and Cell Therapy, Salvador, BA, Brazil / D’Or 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 / D’Or 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 profileengBMCCélulas hepatócitosReprogramação celularCélulas Mesenquimais EstromaisPhenotype 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:FIOCRUZOrge, Iasmim DinizGadd, Victoria L.Barouh, Judah LeãoRossi, Erik AranhaCarvalho, Rejane HughesSmith, IanAllahdadi, Kyan JamesParedes, Bruno DiazSilva, Daniela NascimentoDamasceno, Patrícia Kauanna F.Sampaio, Gabriela LouiseForbes, Stuart J.Soares, Milena Botelho PereiraSouza, Bruno Solano de FreitasLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://arca.fiocruz.br/bitstreams/03263738-80c2-4917-8779-dc5c2a0cc5b5/download5a560609d32a3863062d77ff32785d58MD51falseAnonymousREADORIGINALOrge Yasmin Diniz , Phenotype....pdfOrge Yasmin Diniz , Phenotype....pdfapplication/pdf16650804https://arca.fiocruz.br/bitstreams/11d6e39c-f232-4444-a78f-460aa7b67ae2/downloadc3eb41edf819fec369deb1d2cfc161daMD52trueAnonymousREADOrge Yasmin Diniz , Phenotype....pdfOrge Yasmin Diniz , Phenotype....pdfapplication/pdf16650804https://arca.fiocruz.br/bitstreams/c137e036-adb8-4752-8f6f-d663b7dbd0dc/downloadc3eb41edf819fec369deb1d2cfc161daMD53falseAnonymousREADTEXTOrge Yasmin Diniz , Phenotype....pdf.txtOrge Yasmin Diniz , Phenotype....pdf.txtExtracted texttext/plain56953https://arca.fiocruz.br/bitstreams/c89ba480-6efc-47f7-b268-1ad7b9c148e4/download6e48297d56c7319873001c0429c55c32MD524falseAnonymousREADTHUMBNAILOrge Yasmin Diniz , Phenotype....pdf.jpgOrge Yasmin Diniz , Phenotype....pdf.jpgGenerated Thumbnailimage/jpeg38895https://arca.fiocruz.br/bitstreams/d3b9e7ed-ea15-4f72-941d-4400762d50a3/download7cbca41dd660adf60ac1e886a7a832c9MD525falseAnonymousREADicict/413192025-12-16 06:39:44.211open.accessoai:arca.fiocruz.br:icict/41319https://arca.fiocruz.brRepositório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352025-12-16T09:39:44Repositório Institucional da FIOCRUZ (ARCA) - 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