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PHENOTYPE INSTABILITY OF HEPATOCYTE-LIKE CELLS PRODUCED BY DIRECT REPROGRAMMING OF MESENCHYMAL STROMAL CELLS
Reprogramação celular
Células estromais mesenquimais
Autor
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
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
Afiliación
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 /
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 /
Resumen en ingles
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
Palabras clave en portugues
Células hepatócitosReprogramação celular
Células estromais mesenquimais
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