Patterning the heart, a template for human cardiomyocyte development

Lopes, Susana M. Chuva de Sousa; Hassink, Rutger J.; Feijen, A.; Rooijen, Marga A. van; Doevendans, Pieter A.; Tertoolen, Leon G.J.; Rivière, Aart Brutel de la; Mummery, Christine L.

doi:10.1002/dvdy.20830

Cited by 67 publications

(58 citation statements)

References 53 publications

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“…As an example ( Figure 2B and 2C), the expression of MLC2V (MYL2) was most robust in hA-VCMs and hF-VCMs but present at lower levels in hESCVCMs and the atrial samples (hF-ACMs and hA-ACMs), and was virtually absent in undifferentiated hESCs. These data were entirely consistent with trends reported previously using other techniques, [22][23][24][25] validating the use of this approach for identifying novel proteomic differences.…”

Section: Resultssupporting

confidence: 91%

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

Poon

Keung

Liang

et al. 2015

Circ Cardiovasc Genet

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Background-Differentiation of pluripotent human embryonic stem cells (hESCs) to the cardiac lineage represents a potentially unlimited source of ventricular cardiomyocytes (VCMs), but hESC-VCMs are developmentally immature. Previous attempts to profile hESC-VCMs primarily relied on transcriptomic approaches, but the global proteome has not been examined. Furthermore, most hESC-CM studies focus on pathways important for cardiac differentiation, rather than regulatory mechanisms for CM maturation. We hypothesized that gene products and pathways crucial for maturation can be identified by comparing the proteomes of hESCs, hESC-derived VCMs, human fetal and human adult ventricular and atrial CMs. Methods and Results-Using two-dimensional-differential-in-gel electrophoresis, 121 differentially expressed (>1.5-fold; P<0.05) proteins were detected. The data set implicated a role of the peroxisome proliferator-activated receptor α signaling in cardiac maturation. Consistently, WY-14643, a peroxisome proliferator-activated receptor α agonist, increased fatty oxidative enzyme level, hyperpolarized mitochondrial membrane potential and induced a more organized morphology. Along this line, treatment with the thyroid hormone triiodothyronine increased the dynamic tension developed in engineered human ventricular cardiac microtissue by 3-fold, signifying their maturation. Conclusions-We conclude that the peroxisome proliferator-activated receptor α and thyroid hormone pathways modulate the metabolism and maturation of hESC-VCMs and their engineered tissue constructs. These results may lead to mechanism-based methods for deriving mature chamber-specific CMs.

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Section: Resultssupporting

confidence: 91%

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

Poon

Keung

Liang

et al. 2015

Circ Cardiovasc Genet

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“…Transgenic reporter/ventricular promoters {e.g. MLC2v (ventricular myosin light chain 2), PLN (phospholamban) and RYR2 (ryanodine receptor 2) [46]} may prove a viable approach. Alternatively, development of next-generation technologies such as Raman micro-spectrocopy may allow label-free non-invasive isolation of ventricular myocytes.…”

Section: Enrichment Of Hesc-cardiomyocytesmentioning

confidence: 99%

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Dick

Rajamohan

Ronksley

et al. 2010

Biochemical Society Transactions

104

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Functional cardiomyocytes can now be derived routinely from hPSCs (human pluripotent stem cells), which collectively include embryonic and induced pluripotent stem cells. This technology presents new opportunities to develop pharmacologically relevant in vitro screens to detect cardiotoxicity, with a view to improving patient safety while reducing the economic burden to industry arising from high drug attrition rates. In the present article, we consider the need for human cardiomyocytes in drug-screening campaigns and review the strategies used to differentiate hPSCs towards the cardiac lineage. During early stages of differentiation, hPSC-cardiomyocytes display gene expression profiles, ultra-structures, ion channel functionality and pharmacological responses reminiscent of an embryonic phenotype, but maturation during extended time in culture has been demonstrated convincingly. Notably, hPSC-cardiomyocytes have been shown to respond in a highly predictable manner to over 40 compounds that have a known pharmacological effect on the human heart. This suggests that further development and validation of the hPSC-cardiomyocyte model as a tool for assessing cardiotoxicity is warranted.

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“…28 Human fetal hearts were collected after elective abortion and with informed consent as previously. 29 Biopsies from adult human cardiac tissue were obtained from the Pathology Department after autopsy. Formalin-fixed samples were embedded in paraffin, and 6-m sections were used for immunohistochemical analysis.…”

Section: Isolation and Processing Of Heartsmentioning

confidence: 99%

Endoglin Has a Crucial Role in Blood Cell–Mediated Vascular Repair

et al. 2006

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Background-Endoglin, an accessory receptor for transforming growth factor-␤ in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity. Methods and Results-In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng ϩ/Ϫ ) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng ϩ/Ϫ mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. Conclusions-These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.

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Patterning the heart, a template for human cardiomyocyte development

Cited by 67 publications

References 53 publications

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

Proteomic Analysis of Human Pluripotent Stem Cell–Derived, Fetal, and Adult Ventricular Cardiomyocytes Reveals Pathways Crucial for Cardiac Metabolism and Maturation

Evaluating the utility of cardiomyocytes from human pluripotent stem cells for drug screening

Endoglin Has a Crucial Role in Blood Cell–Mediated Vascular Repair

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