scholarly journals Carfilzomib Treatment Causes Molecular and Functional Alterations of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes

2021 ◽  
Author(s):  
Parvin Forghani ◽  
Aysha Rashid ◽  
Fangxu Sun ◽  
Rui Liu ◽  
Dong Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Molecular Mechanisms ◽  
Cell Model ◽  
Induced Pluripotent Stem Cell ◽  
Cardiac Contraction ◽  
Functional Changes ◽  
Cardiac Side Effects ◽  
Expression Of Genes ◽  
Induced Pluripotent

Background Anticancer therapies have significantly improved patient outcomes; however, cardiac side effects from cancer therapies remain a significant challenge. Cardiotoxicity following treatment with proteasome inhibitors such as carfilzomib is known in clinical settings, but the underlying mechanisms have not been fully elucidated. Methods and Results Using human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) as a cell model for drug‐induced cytotoxicity in combination with traction force microscopy, functional assessments, high‐throughput imaging, and comprehensive omic analyses, we examined the molecular mechanisms involved in structural and functional alterations induced by carfilzomib in hiPSC‐CMs. Following the treatment of hiPSC‐CMs with carfilzomib at 0.01 to 10 µmol/L, we observed a concentration‐dependent increase in carfilzomib‐induced toxicity and corresponding morphological, structural, and functional changes. Carfilzomib treatment reduced mitochondrial membrane potential, ATP production, and mitochondrial oxidative respiration and increased mitochondrial oxidative stress. In addition, carfilzomib treatment affected contractility of hiPSC‐CMs in 3‐dimensional microtissues. At a single cell level, carfilzomib treatment impaired Ca 2+ transients and reduced integrin‐mediated traction forces as detected by piconewton tension sensors. Transcriptomic and proteomic analyses revealed that carfilzomib treatment downregulated the expression of genes involved in extracellular matrices, integrin complex, and cardiac contraction, and upregulated stress responsive proteins including heat shock proteins. Conclusions Carfilzomib treatment causes deleterious changes in cellular and functional characteristics of hiPSC‐CMs. Insights into these changes could be gained from the changes in the expression of genes and proteins identified from our omic analyses.

scholarly journals NRF2 is required for structural and metabolic maturation of human induced pluripotent stem cell-derived ardiomyocytes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xinyuan Zhang ◽  
Liang Ye ◽  
Hao Xu ◽  
Qin Zhou ◽  
Bin Tan ◽  
...  
Keyword(s):  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
Induced Pluripotent Stem Cell ◽  
Metabolic Energy ◽  
Cell Maturation ◽  
Great Promise ◽  
Functional Changes ◽  
Induced Pluripotent

Abstract Background Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great promise for regenerative medicine and in drugs screening. Despite displaying key cardiomyocyte phenotypic characteristics, they more closely resemble fetal/neonatal cardiomyocytes and are still immature; these cells mainly rely on glucose as a substrate for metabolic energy, while mature cardiomyocytes mainly employ oxidative phosphorylation of fatty acids. Studies showed that the alteration of metabolism pattern from glycolysis to oxidative phosphorylation improve the maturity of hiPSC-CMs. As a transcription factor, accumulating evidences showed the important role of NRF2 in the regulation of energy metabolism, which directly regulates the expression of mitochondrial respiratory complexes. Therefore, we hypothesized that NRF2 is involved in the maturation of hiPSC-CMs. Methods The morphological and functional changes related to mitochondria and cell maturation were analyzed by knock-down and activation of NRF2. Results The results showed that the inhibition of NRF2 led to the retardation of cell maturation. The activation of NRF2 leads to a more mature hiPSC-CMs phenotype, as indicated by the increase of cardiac maturation markers, sarcomere length, calcium transient dynamics, the number and fusion events of mitochondria, and mitochondrial respiration. Bioinformatics analysis showed that in addition to metabolism-related genes, NRF2 also activates the expression of myocardial ion channels. Conclusions These findings indicated that NRF2 plays an important role in the maturation of hiPSC-CMs. The present work provides greater insights into the molecular regulation of hiPSC-CMs metabolism and theoretical basis in drug screening, disease modeling, and alternative treatment.

Abstract 14908: Anatomic Validation of Induced Pluripotent Stem Cell-derived Aortic Smooth Muscle Cell Model of Loeys Dietz Syndrome

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Albert J Pedroza ◽  
Samantha Churovich ◽  
Nobu Yokoyama ◽  
Ken Nakamura ◽  
Cristiana Iosef Husted ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Stem Cell ◽  
Aortic Root ◽  
Pluripotent Stem Cell ◽  
Cell Model ◽  
Expression Profiles ◽  
Induced Pluripotent Stem Cell ◽  
Aortic Root Aneurysm ◽  
Ligand Expression ◽  
Induced Pluripotent

Introduction: Mutations in TGF-beta (TGF-ß) signaling genes lead to aortic root aneurysm in Loeys Dietz syndrome (LDS). Smooth muscle cells (SMCs) in the proximal aorta develop from two embryologic origins: second heart field (SHF) and neural crest (NC). Induced pluripotent stem cell (iPSC) models simulate these lineages, but direct correlation to clinical disease is lacking. Hypothesis: iPSC-derived SMCs accurately model lineage-specific aortopathy in LDS. Methods: We generated SMC lines from root and ascending aortic surgical tissue and iPSC-derived SMCs through SHF and NC-specific pathways from an LDS patient ( TGFBR1 mutation). Lineage-specific TGF-ß responses were determined by western blot/ELISA. RNA sequencing and RT-PCR identified SMC transcriptomes. Results: Aortic root SMCs showed greater canonical TGF-ß activation (p-SMAD2/3) versus ascending at baseline and with TGF-ß stimulation ( Figure ). Synonymous results were seen in SHF versus NC SMCs from the iPSC pathway. RNAseq identified 1,600 differentially expressed genes between iPSC lineages, including altered TGF-ß receptor and ligand expression profiles. Primary aortic lines validated iPSC data: root SMCs showed enriched TGF-ß receptor 1/2/3 expression (1.7-, 3.9- and 5.9-fold) while ascending SMCs overexpressed TGFB1 and TGFB2 ligands (1.8- and 3.5-fold). Despite discordant TGF-ß activation, SMC contractile gene expression was similar between lineages in aortic and iPSC-SMCs, suggesting alternative downstream effects in LDS aneurysm. Conclusion: iPSC-derived SMCs effectively model lineage-specific aortic root aneurysm pathology, validating this model as a tool for mechanistic testing and therapy discovery.

scholarly journals Cardiolipin deficiency affects respiratory chain function and organization in an induced pluripotent stem cell model of Barth syndrome

2013 ◽  
Vol 11 (2) ◽  
pp. 806-819 ◽  
Author(s):  
Jan Dudek ◽  
I-Fen Cheng ◽  
Martina Balleininger ◽  
Frédéric M. Vaz ◽  
Katrin Streckfuss-Bömeke ◽  
...  
Keyword(s):  
Stem Cell ◽  
Respiratory Chain ◽  
Pluripotent Stem Cell ◽  
Cell Model ◽  
Induced Pluripotent Stem Cell ◽  
Barth Syndrome ◽  
Stem Cell Model ◽  
Induced Pluripotent

Brief report: A human induced pluripotent stem cell model of cernunnos deficiency reveals an important role for XLF in the survival of the primitive hematopoietic progenitors

Stem Cells ◽  
2013 ◽  
Vol 31 (9) ◽  
pp. 2015-2023 ◽  
Author(s):  
Katarzyna Tilgner ◽  
Irina Neganova ◽  
Chatchawan Singhapol ◽  
Gabriele Saretzki ◽  
Jumana Yousuf Al-Aama ◽  
...  
Keyword(s):  
Stem Cell ◽  
Pluripotent Stem Cell ◽  
Cell Model ◽  
Induced Pluripotent Stem Cell ◽  
Hematopoietic Progenitors ◽  
Stem Cell Model ◽  
Induced Pluripotent
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