Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling
Abstract Background Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because o...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-07-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-022-03021-9 |
| _version_ | 1817969671736918016 |
|---|---|
| author | Sofija Vučković Rafeeh Dinani Edgar E. Nollet Diederik W. D. Kuster Jan Willem Buikema Riekelt H. Houtkooper Miranda Nabben Jolanda van der Velden Birgit Goversen |
| author_facet | Sofija Vučković Rafeeh Dinani Edgar E. Nollet Diederik W. D. Kuster Jan Willem Buikema Riekelt H. Houtkooper Miranda Nabben Jolanda van der Velden Birgit Goversen |
| author_sort | Sofija Vučković |
| collection | DOAJ |
| description | Abstract Background Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs. Methods Here, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism. Results Matured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage. Conclusions Maturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies. |
| first_indexed | 2024-04-13T20:24:06Z |
| format | Article |
| id | doaj.art-bb40feeeeb3d4261ada3ef35f1e56c6f |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-04-13T20:24:06Z |
| publishDate | 2022-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-bb40feeeeb3d4261ada3ef35f1e56c6f2022-12-22T02:31:25ZengBMCStem Cell Research & Therapy1757-65122022-07-0113111910.1186/s13287-022-03021-9Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modelingSofija Vučković0Rafeeh Dinani1Edgar E. Nollet2Diederik W. D. Kuster3Jan Willem Buikema4Riekelt H. Houtkooper5Miranda Nabben6Jolanda van der Velden7Birgit Goversen8Department of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterDepartment of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterDepartment of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterDepartment of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterDepartment of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterLaboratory Genetic Metabolic Diseases, Amsterdam University Medical Centers, Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam Cardiovascular Sciences, University of AmsterdamDepartments of Genetics & Cell Biology and Clinical Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Center+Department of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterDepartment of Physiology, Amsterdam University Medical Centers, Amsterdam Cardiovascular Sciences, Location VU Medical CenterAbstract Background Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have emerged as a powerful tool for disease modeling, though their immature nature currently limits translation into clinical practice. Maturation strategies increasingly pay attention to cardiac metabolism because of its pivotal role in cardiomyocyte development and function. Moreover, aberrances in cardiac metabolism are central to the pathogenesis of cardiac disease. Thus, proper modeling of human cardiac disease warrants careful characterization of the metabolic properties of iPSC-CMs. Methods Here, we examined the effect of maturation protocols on healthy iPSC-CMs applied in 23 studies and compared fold changes in functional metabolic characteristics to assess the level of maturation. In addition, pathological metabolic remodeling was assessed in 13 iPSC-CM studies that focus on hypertrophic cardiomyopathy (HCM), which is characterized by abnormalities in metabolism. Results Matured iPSC-CMs were characterized by mitochondrial maturation, increased oxidative capacity and enhanced fatty acid use for energy production. HCM iPSC-CMs presented varying degrees of metabolic remodeling ranging from compensatory to energy depletion stages, likely due to the different types of mutations and clinical phenotypes modeled. HCM further displayed early onset hypertrophy, independent of the type of mutation or disease stage. Conclusions Maturation strategies improve the metabolic characteristics of iPSC-CMs, but not to the level of the adult heart. Therefore, a combination of maturation strategies might prove to be more effective. Due to early onset hypertrophy, HCM iPSC-CMs may be less suitable to detect early disease modifiers in HCM and might prove more useful to examine the effects of gene editing and new drugs in advanced disease stages. With this review, we provide an overview of the assays used for characterization of cardiac metabolism in iPSC-CMs and advise on which metabolic assays to include in future maturation and disease modeling studies.https://doi.org/10.1186/s13287-022-03021-9iPSCStem cellsCardiomyocyteMetabolismMaturationHCM |
| spellingShingle | Sofija Vučković Rafeeh Dinani Edgar E. Nollet Diederik W. D. Kuster Jan Willem Buikema Riekelt H. Houtkooper Miranda Nabben Jolanda van der Velden Birgit Goversen Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling Stem Cell Research & Therapy iPSC Stem cells Cardiomyocyte Metabolism Maturation HCM |
| title | Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling |
| title_full | Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling |
| title_fullStr | Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling |
| title_full_unstemmed | Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling |
| title_short | Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling |
| title_sort | characterization of cardiac metabolism in ipsc derived cardiomyocytes lessons from maturation and disease modeling |
| topic | iPSC Stem cells Cardiomyocyte Metabolism Maturation HCM |
| url | https://doi.org/10.1186/s13287-022-03021-9 |
| work_keys_str_mv | AT sofijavuckovic characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT rafeehdinani characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT edgarenollet characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT diederikwdkuster characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT janwillembuikema characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT riekelthhoutkooper characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT mirandanabben characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT jolandavandervelden characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling AT birgitgoversen characterizationofcardiacmetabolisminipscderivedcardiomyocyteslessonsfrommaturationanddiseasemodeling |