Hepatocyte-like cells differentiated from methylmalonic aciduria cblB type induced pluripotent stem cells: A platform for the evaluation of pharmacochaperoning
| Autor: | Briso Montiano, A., Vilas, A., Richard Rodríguez, Eva María, Ruiz Sala, P., Morato, E., Desviat, L. R., Ugarte, M., Rodríguez Pombo, Pilar, Pérez, B. |
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| Rok vydání: | 2021 |
| Předmět: |
Induced Pluripotent Stem Cells
MMA cblB type Drug evaluation Pharmacological chaperones Biología y Biomedicina / Biología Disease cellular model Mutation Hepatocytes Molecular Medicine Animals Humans Proto-Oncogene Proteins c-cbl Molecular Biology Amino Acid Metabolism Inborn Errors Hepatocyte-like cells Adaptor Proteins Signal Transducing Methylmalonic Acid |
| Zdroj: | Biblos-e Archivo. Repositorio Institucional de la UAM instname |
| ISSN: | 1879-260X |
| Popis: | Methylmalonic aciduria cblB type (MMA cblB type, MMAB OMIM #251110), caused by a deficiency in the enzyme ATP:cob(I)alamin adenosyltransferase (ATR, E.C_2. 5.1.17), is a severe metabolic disorder with a poor prognosis despite treatment. We recently described the potential therapeutic use of pharmacological chaperones (PCs) after increasing the residual activity of ATR in patient-derived fibroblasts. The present work reports the successful generation of hepatocyte-like cells (HLCs) differentiated from two healthy and two MMAB induced pluripotent stem cell (iPSC) lines, and the use of this platform for testing the effects of PCs. The MMAB cells produced little ATR, showed reduced residual ATR activity, and had higher concentrations of methylmalonic acid compared to healthy HLCs. Differential proteome analysis revealed the two MMAB HCLs to show reproducible differentiation, but this was not so for the healthy HLCs. Interestingly, PC treatment in combination with vitamin B12 increased the amount of ATR available, and subsequently ATR activity, in both MMAB HLCs. More importantly, the treatment significantly reduced the methylmalonic acid content of both. In summary, the HLC model would appear to be an excellent candidate for the pharmacological testing of the described PCs, for analyzing the effects of new drugs, and investigating the repurposing of older drugs, before testing in animal models This work was funded by the Fundacion ´ Isabel Gemio-Fundaci´ on La Caixa [LCF/PR/PR16/11110018], the Instituto de Salud Carlos III (ISCIII),-European Regional Development Fund [PI19/01155] and the Consejería de Educaci´ on, Juventud y Deporte, Comunidad de Madrid [B2017/BMD3721] |
| Databáze: | OpenAIRE |
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