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A Neurotrophic Factor Receptor GFRA2, a Specific Surface Antigen for Cardiac Progenitor Cells, Regulates the Process of Myocardial Compaction

  • Hidekazu Ishida
  • Shigeru Miyagawa
  • Keiichi Ozono
  • Ken Suzuki
  • Yoshiki Sawa
  • Kenta YashiroEmail author
Open Access
Conference paper
  • 347 Downloads

Abstract

A surface marker specific for cardiac progenitors (CPs) allows the robust isolation of CPs, effectively circumventing the necessity of genetic modification. Recently, we have reported that glial cell line–derived neurotrophic factor receptor alpha 2 (Gfra2), which is anchored to the plasma membrane via Glycosylphosphatidylinositol, specifically marks CPs of both the first and second heart fields within the early mouse embryo [1], identified by single-cell expression profiling on mouse embryonic CPs (Fig. 56.1) [2, 3].

Keywords

GFRA2 Surface antigen Cardiac progenitor cells Non-compaction cardiomyopathy 
A surface marker specific for cardiac progenitors (CPs) allows the robust isolation of CPs, effectively circumventing the necessity of genetic modification. Recently, we have reported that glial cell line–derived neurotrophic factor receptor alpha 2 (Gfra2), which is anchored to the plasma membrane via Glycosylphosphatidylinositol, specifically marks CPs of both the first and second heart fields within the early mouse embryo [1], identified by single-cell expression profiling on mouse embryonic CPs (Fig. 56.1) [2, 3].
  • GFRA2 facilitates the isolation of CPs by fluorescence-activated cell sorting from differentiating mouse and human pluripotent stem cells. If utilizing pan-mesoderm marker PDGFRA and hemangioblastic marker KDR in conjunction with GFRA2, multipotent CPs giving rise to cardiomyocytes, smooth muscle cells and endothelial cells are identified as GFRA2+/PDGFRA+/KDR+ whereas CPs already committed only to cardiomyocytes are identified as GFRA2+/PDGFRA+/KDRneg.

  • In loss-of-function of Gfra2, the functional redundancy of GFRA1 compensated for the cardiac GFRA2 signal in the mutant mouse embryos. Compound mutant of Gfra1/2 showed non-compaction cardiomyopathy due to the down-regulation of NOTCH signal in the developing heart. Cardiac GFRA2 signal is distinct from the canonical pathway that depends on the RET tyrosine kinase and its established ligands.

Fig. 56.1

GFRA2 is a specific marker for CPs which governs myocardial compaction. Upper case: A signal transduction via GFRA1/2 is upstream of NOTCH signal that is indispensable for the myocardial compaction process. Lower case: GFRA2 is a specific surface antigen to identify CPs from differentiating pluripotent stem cells in mice and humans. This illustration is cited from Ishida, H et al. Cell Rep. 2016 Jul 26;16(4):1026–38, and is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ or send a letter to Creative Commons, PO Box 1866, Mountain View, CA 94042, USA

Collectively our findings establish a platform for investigating the biology of CPs as a foundation for the future development of CP transplantation therapies for treating heart failure.

Acknowledgments

This work was supported by MRC New Investigator Research Grant G0900105 and MRC Research Grant MR/J007625/1 to K.Y., Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and JSPS (Japan Society for the Promotion of Science) Postdoctoral Fellowship for Research Abroad to H.I. We thank Ruchaya PJ at Kings College London for the support in writing.

References

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    Ishida H, Saba R, Kokkinopoulos I, et al. GFRA2 identifies cardiac progenitors and mediates cardiomyocyte differentiation in a RET-independent signaling pathway. Cell Rep. 2016;16(4):1026–38.CrossRefGoogle Scholar
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    Brouilette S, Kuersten S, Mein C, et al. A simple and novel method for RNA-seq library preparation of single cell cDNA analysis by hyperactive Tn5 transposase. Dev Dyn. 2012;241(10):1584–90.CrossRefGoogle Scholar
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    Kokkinopoulos I, Ishida H, Saba R, et al. Single-cell expression profiling reveals a dynamic state of cardiac precursor cells in the early mouse embryo. PLoS One. 2015;10(10):e0140831.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2020

Open Access This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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Authors and Affiliations

  • Hidekazu Ishida
    • 1
  • Shigeru Miyagawa
    • 2
  • Keiichi Ozono
    • 1
  • Ken Suzuki
    • 3
  • Yoshiki Sawa
    • 2
  • Kenta Yashiro
    • 4
    • 5
    • 6
    Email author
  1. 1.Department of Paediatrics, Graduate School of MedicineOsaka UniversitySuitaJapan
  2. 2.Department of Cardiovascular Surgery, Graduate School of MedicineOsaka UniversitySuitaJapan
  3. 3.Centre for Microvascular Research, William Harvey Research Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
  4. 4.Department of Cardiac Regeneration and Therapeutics, Graduate School of MedicineOsaka UniversitySuitaJapan
  5. 5.Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
  6. 6.Department of Anatomy, Division of Anatomy and Developmental BiologyKyoto Prefectural University of MedicineKyotoJapan

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