Induced pluripotent stem cells model personalized variations in liver disease resulting from α1‐antitrypsin deficiency
In the classical form of α1‐antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1‐antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain‐of‐function, “proteotoxic” mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates...
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| Published in | Hepatology (Baltimore, Md.) Vol. 62; no. 1; pp. 147 - 157 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.07.2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0270-9139 1527-3350 1527-3350 |
| DOI | 10.1002/hep.27753 |
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| Abstract | In the classical form of α1‐antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1‐antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain‐of‐function, “proteotoxic” mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient‐specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte‐like cells (iHeps) having many characteristics of hepatocytes. Pulse‐chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild‐type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. Conclusion: iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that “proteostasis” mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. (Hepatology 2015;62:147‐157) |
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| AbstractList | In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD.UNLABELLEDIn the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD.iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies.CONCLUSIONiHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain-of-function, "proteotoxic" mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient-specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte-like cells (iHeps) having many characteristics of hepatocytes. Pulse-chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild-type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that "proteostasis" mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. In the classical form of α1‐antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1‐antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain‐of‐function, “proteotoxic” mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient‐specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte‐like cells (iHeps) having many characteristics of hepatocytes. Pulse‐chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild‐type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. Conclusion : iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that “proteostasis” mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. (H epatology 2015;62:147‐157) In the classical form of α1‐antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1‐antitrypsin Z (ATZ) in hepatocytes causes hepatic damage by a gain‐of‐function, “proteotoxic” mechanism. Whereas some ATD patients develop severe liver disease (SLD) that necessitates liver transplantation, others with the same genetic defect completely escape this clinical phenotype. We investigated whether induced pluripotent stem cells (iPSCs) from ATD individuals with or without SLD could model these personalized variations in hepatic disease phenotypes. Patient‐specific iPSCs were generated from ATD patients and a control and differentiated into hepatocyte‐like cells (iHeps) having many characteristics of hepatocytes. Pulse‐chase and endoglycosidase H analysis demonstrate that the iHeps recapitulate the abnormal accumulation and processing of the ATZ molecule, compared to the wild‐type AT molecule. Measurements of the fate of intracellular ATZ show a marked delay in the rate of ATZ degradation in iHeps from SLD patients, compared to those from no liver disease patients. Transmission electron microscopy showed dilated rough endoplasmic reticulum in iHeps from all individuals with ATD, not in controls, but globular inclusions that are partially covered with ribosomes were observed only in iHeps from individuals with SLD. Conclusion: iHeps model the individual disease phenotypes of ATD patients with more rapid degradation of misfolded ATZ and lack of globular inclusions in cells from patients who have escaped liver disease. The results support the concept that “proteostasis” mechanisms, such as intracellular degradation pathways, play a role in observed variations in clinical phenotype and show that iPSCs can potentially be used to facilitate predictions of disease susceptibility for more precise and timely application of therapeutic strategies. (Hepatology 2015;62:147‐157) |
| Author | Tafaleng, Edgar N. Nagaya, Masaki Stolz, Donna B. Hale, Pamela Perlmutter, David H. Roy‐Chowdhury, Jayanta Feghali‐Bostwick, Carol A. Wilson, Andrew A. Kotton, Darrell N. Chakraborty, Souvik Strom, Stephen C. Wu, Wanquan Fox, Ira J. Soto‐Gutierrez, Alejandro Han, Bing |
| Author_xml | – sequence: 1 givenname: Edgar N. orcidid: 0000-0003-3050-515X surname: Tafaleng fullname: Tafaleng, Edgar N. organization: Children's Hospital of Pittsburgh of UPMC – sequence: 2 givenname: Souvik surname: Chakraborty fullname: Chakraborty, Souvik organization: University of Pittsburgh School of Medicine – sequence: 3 givenname: Bing surname: Han fullname: Han, Bing organization: Children's Hospital of Pittsburgh of UPMC – sequence: 4 givenname: Pamela surname: Hale fullname: Hale, Pamela organization: University of Pittsburgh School of Medicine – sequence: 5 givenname: Wanquan surname: Wu fullname: Wu, Wanquan organization: Children's Hospital of Pittsburgh of UPMC – sequence: 6 givenname: Alejandro surname: Soto‐Gutierrez fullname: Soto‐Gutierrez, Alejandro organization: University of Pittsburgh School of Medicine – sequence: 7 givenname: Carol A. surname: Feghali‐Bostwick fullname: Feghali‐Bostwick, Carol A. organization: Medical University of South Carolina – sequence: 8 givenname: Andrew A. surname: Wilson fullname: Wilson, Andrew A. organization: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center – sequence: 9 givenname: Darrell N. surname: Kotton fullname: Kotton, Darrell N. organization: Center for Regenerative Medicine (CReM) of Boston University and Boston Medical Center – sequence: 10 givenname: Masaki surname: Nagaya fullname: Nagaya, Masaki organization: University of Pittsburgh – sequence: 11 givenname: Stephen C. surname: Strom fullname: Strom, Stephen C. organization: Karolinska Institutet – sequence: 12 givenname: Jayanta surname: Roy‐Chowdhury fullname: Roy‐Chowdhury, Jayanta organization: Albert Einstein College of Medicine – sequence: 13 givenname: Donna B. surname: Stolz fullname: Stolz, Donna B. organization: University of Pittsburgh School of Medicine – sequence: 14 givenname: David H. surname: Perlmutter fullname: Perlmutter, David H. organization: University of Pittsburgh School of Medicine – sequence: 15 givenname: Ira J. surname: Fox fullname: Fox, Ira J. organization: University of Pittsburgh |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25690322$$D View this record in MEDLINE/PubMed |
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| Copyright | 2015 by the American Association for the Study of Liver Diseases 2015 by the American Association for the Study of Liver Diseases. |
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| Notes | This work was supported, in part, by the National Institutes of Health (grant no.: PO1 DK096990), the Department of Defense (grant no.: W81XWH‐09‐1‐0658), and Children's Hospital of Pittsburgh of UPMC RAC Predoctoral Fellowship. Potential conflict of interes: Dr. Fox owns stock in Regenerative Medical Solutions. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
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Sep;2(9):641-54 |
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| Snippet | In the classical form of α1‐antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1‐antitrypsin Z (ATZ) in hepatocytes causes... In the classical form of α1-antitrypsin deficiency (ATD), aberrant intracellular accumulation of misfolded mutant α1-antitrypsin Z (ATZ) in hepatocytes causes... |
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| SubjectTerms | alpha 1-Antitrypsin - metabolism alpha 1-Antitrypsin Deficiency - complications Cells, Cultured Endoplasmic Reticulum, Rough - metabolism Humans Induced Pluripotent Stem Cells - metabolism Liver Diseases - etiology Liver Diseases - metabolism |
| Title | Induced pluripotent stem cells model personalized variations in liver disease resulting from α1‐antitrypsin deficiency |
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