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http://hdl.handle.net/10261/295514
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Campo DC | Valor | Lengua/Idioma |
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dc.contributor.author | Kaserman, Joseph E. | - |
dc.contributor.author | Werder, Rhiannon B. | - |
dc.contributor.author | Wang, Feiya | - |
dc.contributor.author | Matte, Taylor | - |
dc.contributor.author | Higgins, Michelle I. | - |
dc.contributor.author | Dodge, Mark | - |
dc.contributor.author | Lindstrom-Vautrin, Jonathan | - |
dc.contributor.author | Bawa, Pushpinder | - |
dc.contributor.author | Hinds, Anne | - |
dc.contributor.author | Bullitt, Esther | - |
dc.contributor.author | Caballero, Ignacio S. | - |
dc.contributor.author | Shi, Xu | - |
dc.contributor.author | Gerszten, Robert E. | - |
dc.contributor.author | Brunetti-Pierri, Nicola | - |
dc.contributor.author | Liesa, Marc | - |
dc.contributor.author | Villacorta-Martin, Carlos | - |
dc.contributor.author | Hollenberg, Anthony N. | - |
dc.contributor.author | Kotton, Darrell N. | - |
dc.contributor.author | Wilson, Andrew A. | - |
dc.date.accessioned | 2023-02-21T16:31:53Z | - |
dc.date.available | 2023-02-21T16:31:53Z | - |
dc.date.issued | 2022-12-06 | - |
dc.identifier | doi: 10.1016/j.celrep.2022.111775 | - |
dc.identifier | issn: 2211-1247 | - |
dc.identifier.citation | Cell Reports 41(10): 111775 (2022) | - |
dc.identifier.uri | http://hdl.handle.net/10261/295514 | - |
dc.description.abstract | Individuals homozygous for the “Z” mutation in alpha-1 antitrypsin deficiency are known to be at increased risk for liver disease. It has also become clear that some degree of risk is similarly conferred by the heterozygous state. A lack of model systems that recapitulate heterozygosity in human hepatocytes has limited the ability to study the impact of a single Z alpha-1 antitrypsin (ZAAT) allele on hepatocyte biology. Here, we describe the derivation of syngeneic induced pluripotent stem cells (iPSCs) engineered to determine the effects of ZAAT heterozygosity in iPSC-hepatocytes (iHeps). We find that heterozygous MZ iHeps exhibit an intermediate disease phenotype and share with ZZ iHeps alterations in AAT protein processing and downstream perturbations including altered endoplasmic reticulum (ER) and mitochondrial morphology, reduced mitochondrial respiration, and branch-specific activation of the unfolded protein response in cell subpopulations. Our model of MZ heterozygosity thus provides evidence that a single Z allele is sufficient to disrupt hepatocyte homeostatic function. | - |
dc.description.sponsorship | This work was supported by an Alpha-1 Foundation John W. Walsh Translational Research Award (to J.E.K.); a CJ Martin Early Career Fellowship from the Australian National Health and Medical Research Council (to R.B.W.); NIH grant R01HL095993 (to D.N.K.); and NIH grants R01DK101501 (to A.A.W.) and R01DK117940 (to A.N.H. and A.A.W.). iPSC distribution and disease modeling is supported by NIH grants U01TR001810 (to D.N.K. and A.A.W.) and N0175N92020C00005 (to D.N.K.); and by The Alpha-1 Project (TAP), a wholly owned subsidiary of the Alpha-1 Foundation (to D.N.K. and A.A.W.). | - |
dc.format | application/pdf | - |
dc.language | eng | - |
dc.publisher | Cell Press | - |
dc.relation.isversionof | Publisher's version | - |
dc.relation.isbasedon | Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity [Dataset]; 2022; Kaserman, Joseph E.; Werder, Rhiannon B.; Wang, Feiya; Matte, Taylor; Higgins, Michelle I.; Dodge, Mark; Lindstrom-Vautrin, Jonathan; Bawa, Pushpinder; Hinds, Anne; Bullitt, Esther; Caballero, Ignacio S.; Shi, Xu; Gerszten, Robert E.; Brunetti-Pierri, Nicola; Liesa, Marc; Villacorta-Martin, Carlos; Hollenberg, Anthony N.; Kotton, Darrell N.; Wilson, Andrew A.; Cell Press; http://dx.doi.org/10.1016/j.celrep.2022.111775 | - |
dc.rights | openAccess | - |
dc.subject | Induced pluripotent stem cells | - |
dc.subject | iPSC-derived hepatocytes | - |
dc.subject | Alpha-1 antitrypsin deficiency | - |
dc.subject | ER stress | - |
dc.subject | Proteostasis | - |
dc.subject | Unfolded protein response | - |
dc.subject | Metabolic dysregulation | - |
dc.subject | Mitochondrial dysfunction | - |
dc.subject | Liver fibrosis | - |
dc.subject | Cellular heterogeneity | - |
dc.title | Human iPSC-hepatocyte modeling of alpha-1 antitrypsin heterozygosity reveals metabolic dysregulation and cellular heterogeneity | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1016/j.celrep.2022.111775 | es_ES |
dc.relation.publisherversion | http://dx.doi.org/10.1016/j.celrep.2022.111775 | - |
dc.date.updated | 2023-02-21T16:31:53Z | - |
dc.rights.license | https://creativecommons.org/licenses/by-nc-nd/4.0/ | - |
dc.contributor.funder | National Health and Medical Research Council (Australia) | - |
dc.contributor.funder | National Institutes of Health (US) | - |
dc.contributor.funder | Alpha- Foundation | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/100013594 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100000925 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100000002 | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.openairetype | artículo | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | open | - |
item.fulltext | With Fulltext | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
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