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Derivation of Cardiac Progenitor Cells from Embryonic Stem Cells
Published on: January 12, 2015
The differentiation of cardiomyocytes from mouse embryonic stem cells is altered by dioxin
Tui Neri1, Valeria Merico, Fabio Fiordaliso
1Laboratorio di Biologia dello Sviluppo, Dipartimento di Biologia Animale, Universita' degli Studi di Pavia, Via Ferrata 9, 27100 Pavia, Italy.
Abstract:
2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) causes abnormalities during heart development. Cardiomyocytes derived from embryonic stem (ES) cells are a robust model for the study of early cardiomyogenesis. Here, we evaluated the effects of TCDD at key stages during the differentiation of mouse ES cells into cardiomyocytes analysing: (i) the transcription of lineage differentiation (Brachyury, Nkx-2.5, Actc-1), cardiac-specific (Alpk3, cTnT, cTnI, cTnC) and detoxification phase I (Cyp1A1, Cyp1A2 and Cyp1B1) and phase II (Nqo1, Gsta1 and Ugt1a6) genes; (ii) the global gene expression; (iii) the ultrastructure of ES-derived cardiomyocytes; (iv) level of ATP production and (v) the immunolocalisation of sarcomeric α-actinin, β-myosin heavy chain and cTnT proteins. We show that TCDD affects the differentiation of ES cells into cardiomyocytes at several levels: (1) induces the expression of phase I genes; (2) down-regulates a group of heart-specific genes, some involved in the oxidative phosphorylation pathway; (3) reduces the efficiency of differentiation; (4) alters the arrangement of mitochondria, that show twisted and disrupted cristae, and of some sarcomeres, with misalignement or disarrangement of the myofibrillar organisation and (5) reduces ATP production. This study provides novel evidences that TCDD impairs cardiomyocyte differentiation. Sarcomeres and mitochondria could be a target for dioxin toxicity, their disruption representing a possible mechanism developing cardiac injury.
Insights
2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) exposure disrupts embryonic stem cell differentiation into cardiomyocytes. TCDD impairs heart development by affecting gene expression, cellular structure, and ATP production, highlighting sarcomeres and mitochondria as potential targets for dioxin toxicity.
Area of Science:
- Developmental Biology
- Toxicology
- Stem Cell Biology
Background:
- 2,3,7,8-Tetrachlorodibenzo-para-dioxin (TCDD) is a known teratogen that can cause abnormalities during heart development.
- Embryonic stem (ES) cell-derived cardiomyocytes offer a valuable model for studying early cardiomyogenesis and the impact of environmental toxins.
Purpose of the Study:
- To investigate the effects of TCDD on mouse ES cell differentiation into cardiomyocytes.
- To analyze TCDD's impact on key molecular, cellular, and functional aspects of cardiomyogenesis.
Main Methods:
- Analysis of gene transcription for lineage, cardiac-specific, and detoxification genes.
- Global gene expression profiling.
- Assessment of cardiomyocyte ultrastructure, ATP production, and protein immunolocalization.
Main Results:
- TCDD induced phase I detoxification genes and downregulated cardiac-specific genes, including those in oxidative phosphorylation.
- Reduced differentiation efficiency, altered mitochondrial and sarcomere organization, and decreased ATP production were observed.
- TCDD exposure led to significant disruptions in cardiomyocyte development and function.
Conclusions:
- TCDD impairs cardiomyocyte differentiation from mouse ES cells.
- Sarcomeres and mitochondria are identified as potential cellular targets for TCDD-induced cardiotoxicity.
- Disruption of these structures may contribute to the mechanism of dioxin-related cardiac injury.
