Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells

Abstract Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype–phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this ne...

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Autores principales:	Cristiana Iosef, Albert J. Pedroza, Jason Z. Cui, Alex R. Dalal, Mamoru Arakawa, Yasushi Tashima, Tiffany K. Koyano, Grayson Burdon, Samantha M. P. Churovich, Joshua O. Orrick, Mitchel Pariani, Michael P. Fischbein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5f51d52d33394a82b68928fa4c927f13
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spelling	oai:doaj.org-article:5f51d52d33394a82b68928fa4c927f132021-12-02T12:34:03ZQuantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells10.1038/s41598-020-77274-w2045-2322https://doaj.org/article/5f51d52d33394a82b68928fa4c927f132020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-77274-whttps://doaj.org/toc/2045-2322Abstract Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype–phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin αV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.Cristiana IosefAlbert J. PedrozaJason Z. CuiAlex R. DalalMamoru ArakawaYasushi TashimaTiffany K. KoyanoGrayson BurdonSamantha M. P. ChurovichJoshua O. OrrickMitchel ParianiMichael P. FischbeinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristiana Iosef Albert J. Pedroza Jason Z. Cui Alex R. Dalal Mamoru Arakawa Yasushi Tashima Tiffany K. Koyano Grayson Burdon Samantha M. P. Churovich Joshua O. Orrick Mitchel Pariani Michael P. Fischbein Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
description	Abstract Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the FBN1 gene that produces wide disease phenotypic variability. The lack of ample genotype–phenotype correlation hinders translational study development aimed at improving disease prognosis. In response to this need, an induced pluripotent stem cell (iPSC) disease model has been used to test patient-specific cells by a proteomic approach. This model has the potential to risk stratify patients to make clinical decisions, including timing for surgical treatment. The regional propensity for aneurysm formation in MFS may be related to distinct smooth muscle cell (SMC) embryologic lineages. Thus, peripheral blood mononuclear cell (PBMC)-derived induced pluripotent stem cells (iPSC) were differentiated into lateral mesoderm (LM, aortic root) and neural crest (NC, ascending aorta/transverse arch) SMC lineages to model MFS aortic pathology. Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) proteomic analysis by tandem mass spectrometry was applied to profile LM and NC iPSC SMCs from four MFS patients and two healthy controls. Analysis revealed 45 proteins with lineage-dependent expression in MFS patients, many of which were specific to diseased samples. Single protein-level data from both iPSC SMCs and primary MFS aortic root aneurysm tissue confirmed elevated integrin αV and reduced MRC2 in clinical disease specimens, validating the iPSC iTRAQ findings. Functionally, iPSC SMCs exhibited defective adhesion to a variety of extracellular matrix proteins, especially laminin-1 and fibronectin, suggesting altered cytoskeleton dynamics. This study defines the aortic embryologic origin-specific proteome in a validated iPSC SMC model to identify novel protein markers associated with MFS aneurysm phenotype. Translating iPSC findings into clinical aortic aneurysm tissue samples highlights the potential for iPSC-based methods to model MFS disease for mechanistic studies and therapeutic discovery in vitro.
format	article
author	Cristiana Iosef Albert J. Pedroza Jason Z. Cui Alex R. Dalal Mamoru Arakawa Yasushi Tashima Tiffany K. Koyano Grayson Burdon Samantha M. P. Churovich Joshua O. Orrick Mitchel Pariani Michael P. Fischbein
author_facet	Cristiana Iosef Albert J. Pedroza Jason Z. Cui Alex R. Dalal Mamoru Arakawa Yasushi Tashima Tiffany K. Koyano Grayson Burdon Samantha M. P. Churovich Joshua O. Orrick Mitchel Pariani Michael P. Fischbein
author_sort	Cristiana Iosef
title	Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
title_short	Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
title_full	Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
title_fullStr	Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
title_full_unstemmed	Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells
title_sort	quantitative proteomics reveal lineage-specific protein profiles in ipsc-derived marfan syndrome smooth muscle cells
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5f51d52d33394a82b68928fa4c927f13
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Quantitative proteomics reveal lineage-specific protein profiles in iPSC-derived Marfan syndrome smooth muscle cells

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