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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Stage specific transcriptome profiles at cardiac lineage commitment during cardiomyocyte differentiation from mouse and human pluripotent stem cells

  • Cho, Sung Woo (Division of Cardiology, Department of Internal Medicine, Inje University College of Medicine, Ilsan Paik Hospital Vision 21 Cardiac & Vascular Center) ;
  • Kim, Hyoung Kyu (Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutics Center, Inje University College of Medicine) ;
  • Sung, Ji Hee (Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutics Center, Inje University College of Medicine) ;
  • Han, Jin (Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutics Center, Inje University College of Medicine)
  • Received : 2021.04.01
  • Accepted : 2021.05.01
  • Published : 2021.09.30
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Abstract

Cardiomyocyte differentiation occurs through complex and finely regulated processes including cardiac lineage commitment and maturation from pluripotent stem cells (PSCs). To gain some insight into the genome-wide characteristics of cardiac lineage commitment, we performed transcriptome analysis on both mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs) at specific stages of cardiomyocyte differentiation. Specifically, the gene expression profiles and the protein-protein interaction networks of the mESC-derived platelet-derived growth factor receptor-alpha (PDGFRα)+ cardiac lineage-committed cells (CLCs) and hiPSC-derived kinase insert domain receptor (KDR)+ and PDGFRα+ cardiac progenitor cells (CPCs) at cardiac lineage commitment were compared with those of mesodermal cells and differentiated cardiomyocytes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses revealed that the genes significantly upregulated at cardiac lineage commitment were associated with responses to organic substances and external stimuli, extracellular and myocardial contractile components, receptor binding, gated channel activity, PI3K-AKT signaling, and cardiac hypertrophy and dilation pathways. Protein-protein interaction network analysis revealed that the expression levels of genes that regulate cardiac maturation, heart contraction, and calcium handling showed a consistent increase during cardiac differentiation; however, the expression levels of genes that regulate cell differentiation and multicellular organism development decreased at the cardiac maturation stage following lineage commitment. Additionally, we identified for the first time the protein-protein interaction network connecting cardiac development, the immune system, and metabolism during cardiac lineage commitment in both mESC-derived PDGFRα+ CLCs and hiPSC-derived KDR+PDGFRα+ CPCs. These findings shed light on the regulation of cardiac lineage commitment and the pathogenesis of cardiometabolic diseases.

Keywords

Acknowledgement

This study was funded by the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Education (2017R1D1A3B03034465), the NRF of Korea funded by the Ministry of Science and ICT (2020R1C1C1015104), and 2017 and 2018 Inje University research grants.

References

  1. Burridge PW, Keller G, Gold JD, Wu JC (2012) Production of de novo cardiomyocytes: human pluripotent stem cell differentiation and direct reprogramming. Cell Stem Cell 10, 16-28 https://doi.org/10.1016/j.stem.2011.12.013
  2. Cho SW, Park JS, Heo HJ et al (2014) Dual modulation of the mitochondrial permeability transition pore and redox signaling synergistically promotes cardiomyocyte differentiation from pluripotent stem cells. J Am Heart Assoc 3, e000693 https://doi.org/10.1161/JAHA.113.000693
  3. Robertson C, Tran DD, George SC (2013) Concise review: maturation phases of human pluripotent stem cell-derived cardiomyocytes. Stem Cells 31, 829-837 https://doi.org/10.1002/stem.1331
  4. Uosaki H, Cahan P, Lee DI et al (2015) Transcriptional landscape of cardiomyocyte maturation. Cell Rep 13, 1705-1716 https://doi.org/10.1016/j.celrep.2015.10.032
  5. Kattman SJ, Witty AD, Gagliardi M et al (2011) Stage-specific optimization of activin/nodal and BMP signaling promotes cardiac differentiation of mouse and human pluripotent stem cell lines. Cell Stem Cell 8, 228-240 https://doi.org/10.1016/j.stem.2010.12.008
  6. Takeda M, Kanki Y, Masumoto H et al (2018) Identification of cardiomyocyte-fated progenitors from human-induced pluripotent stem cells marked with CD82. Cell Rep 22, 546-556 https://doi.org/10.1016/j.celrep.2017.12.057
  7. Hong SP, Song S, Cho SW et al (2017) Generation of PDGFRalpha(+) cardioblasts from pluripotent stem cells. Sci Rep 7, 41840 https://doi.org/10.1038/srep41840
  8. Hong SP, Song S, Lee S et al (2019) Regenerative potential of mouse embryonic stem cell-derived PDGFRalpha(+) cardiac lineage committed cells in infarcted myocardium. World J Stem Cells 11, 44-54 https://doi.org/10.4252/wjsc.v11.i1.44
  9. Liu Q, Jiang C, Xu J et al (2017) Genome-wide temporal profiling of transcriptome and open chromatin of early cardiomyocyte differentiation derived from hiPSCs and hESCs. Circ Res 121, 376-391 https://doi.org/10.1161/CIRCRESAHA.116.310456
  10. Leitolis A, Robert AW, Pereira IT, Correa A, Stimamiglio MA (2019) Cardiomyogenesis modeling using pluripotent stem cells: the role of microenvironmental signaling. Front Cell Dev Biol 7, 164 https://doi.org/10.3389/fcell.2019.00164
  11. Seo HR, Joo HJ, Kim DH et al (2017) Nanopillar surface topology promotes cardiomyocyte differentiation through cofilin-mediated cytoskeleton rearrangement. ACS Appl Mater Interfaces 9, 16803-16812 https://doi.org/10.1021/acsami.7b01555
  12. Robert AW, Pereira IT, Dallagiovanna B, Stimamiglio MA (2020) Secretome analysis performed during in vitro cardiac differentiation: discovering the cardiac microenvironment. Front Cell Dev Biol 8, 49 https://doi.org/10.3389/fcell.2020.00049
  13. Naito AT, Akazawa H, Takano H et al (2005) Phosphatidylinositol 3-kinase-Akt pathway plays a critical role in early cardiomyogenesis by regulating canonical Wnt signaling. Circ Res 97, 144-151 https://doi.org/10.1161/01.RES.0000175241.92285.f8
  14. Samakova A, Gazova A, Sabova N, Valaskova S, Jurikova M, Kyselovic J (2019) The PI3k/Akt pathway is associated with angiogenesis, oxidative stress and survival of mesenchymal stem cells in pathophysiologic condition in ischemia. Physiol Res 68, S131-S138
  15. Yang J, Savvatis K, Kang JS et al (2016) Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun 7, 13710 https://doi.org/10.1038/ncomms13710
  16. D'Amico MA, Ghinassi B, Izzicupo P, Di Ruscio A, Di Baldassarre A (2016) IL-6 activates PI3K and PKCzeta signaling and determines cardiac differentiation in rat embryonic H9c2 cells. J Cell Physiol 231, 576-586 https://doi.org/10.1002/jcp.25101
  17. Ibarra-Ibarra BR, Franco M, Paez A, Lopez EV, Masso F (2019) Improved efficiency of cardiomyocyte-like cell differentiation from rat adipose tissue-derived mesenchymal stem cells with a directed differentiation protocol. Stem Cells Int 2019, 8940365 https://doi.org/10.1155/2019/8940365
  18. Bartekova M, Radosinska J, Jelemensky M, Dhalla NS (2018) Role of cytokines and inflammation in heart function during health and disease. Heart Fail Rev 23, 733-758 https://doi.org/10.1007/s10741-018-9716-x
  19. Yang Y, Lv J, Jiang S et al (2016) The emerging role of toll-like receptor 4 in myocardial inflammation. Cell Death Dis 7, e2234 https://doi.org/10.1038/cddis.2016.140
  20. Zhang X, Cao YJ, Zhang HY, Cong H, Zhang J (2019) Associations between ADIPOQ polymorphisms and coronary artery disease: a meta-analysis. BMC Cardiovasc Disord 19, 63 https://doi.org/10.1186/s12872-019-1041-3
  21. Furuhashi M (2019) Fatty acid-binding protein 4 in cardiovascular and metabolic diseases. J Atheroscler Thromb 26, 216-232 https://doi.org/10.5551/jat.48710
  22. Graff EC, Fang H, Wanders D, Judd RL (2016) Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2. Metabolism 65, 102-113 https://doi.org/10.1016/j.metabol.2015.10.001
  23. Pan X, Wen SW, Bestman PL, Kaminga AC, Acheampong K, Liu A (2020) Fetuin-a in metabolic syndrome: a systematic review and meta-analysis. PLoS One 15, e0229776 https://doi.org/10.1371/journal.pone.0229776
  24. Anzai T, Yamagata T, Uosaki H (2020) Comparative transcriptome landscape of mouse and human hearts. Front Cell Dev Biol 8, 268 https://doi.org/10.3389/fcell.2020.00268