GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Hidekazu Ishida; Rie Saba; Ioannis Kokkinopoulos; Masakazu Hashimoto; Osamu Yamaguchi; Sonja Nowotschin; Manabu Shiraishi; Prashant Ruchaya; Duncan Miller; Stephen Harmer; Ariel Poliandri; Shigetoyo Kogaki; Yasushi Sakata; Leo Dunkel; Andrew Tinker; Anna-Katerina Hadjantonakis; Yoshiki Sawa; Hiroshi Sasaki; Keiichi Ozono; Ken Suzuki; Kenta Yashiro

doi:10.1016/j.celrep.2016.06.050

GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Hidekazu Ishida, Rie Saba, Ioannis Kokkinopoulos, Masakazu Hashimoto, Osamu Yamaguchi, Sonja Nowotschin, Manabu Shiraishi, Prashant Ruchaya, Duncan Miller, Stephen Harmer, Ariel Poliandri, Shigetoyo Kogaki, Yasushi Sakata, Leo Dunkel, Andrew Tinker, Anna-Katerina Hadjantonakis, Yoshiki Sawa, Hiroshi Sasaki, Keiichi Ozono, Ken SuzukiKenta Yashiro

School of Physiology, Pharmacology & Neuroscience

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Abstract

A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

Original language	English
Pages (from-to)	1026-1038
Number of pages	13
Journal	Cell Reports
Volume	16
Issue number	4
Early online date	26 Jul 2016
DOIs	https://doi.org/10.1016/j.celrep.2016.06.050
Publication status	Published - 26 Jul 2016

Bibliographical note

Keywords

Animals
Cell Differentiation/physiology
Cells, Cultured
Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism
Glycosylphosphatidylinositols/metabolism
Humans
Ligands
Mice
Myocytes, Cardiac/metabolism
Organogenesis/physiology
Pluripotent Stem Cells/metabolism
Proto-Oncogene Proteins c-ret/metabolism
Receptor Protein-Tyrosine Kinases/metabolism
Signal Transduction/physiology

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Ishida, H., Saba, R., Kokkinopoulos, I., Hashimoto, M., Yamaguchi, O., Nowotschin, S., Shiraishi, M., Ruchaya, P., Miller, D., Harmer, S., Poliandri, A., Kogaki, S., Sakata, Y., Dunkel, L., Tinker, A., Hadjantonakis, A.-K., Sawa, Y., Sasaki, H., Ozono, K., ... Yashiro, K. (2016). GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway. Cell Reports, 16(4), 1026-1038. https://doi.org/10.1016/j.celrep.2016.06.050

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title = "GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway",

abstract = "A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.",

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author = "Hidekazu Ishida and Rie Saba and Ioannis Kokkinopoulos and Masakazu Hashimoto and Osamu Yamaguchi and Sonja Nowotschin and Manabu Shiraishi and Prashant Ruchaya and Duncan Miller and Stephen Harmer and Ariel Poliandri and Shigetoyo Kogaki and Yasushi Sakata and Leo Dunkel and Andrew Tinker and Anna-Katerina Hadjantonakis and Yoshiki Sawa and Hiroshi Sasaki and Keiichi Ozono and Ken Suzuki and Kenta Yashiro",

year = "2016",

month = jul,

day = "26",

doi = "10.1016/j.celrep.2016.06.050",

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Ishida, H, Saba, R, Kokkinopoulos, I, Hashimoto, M, Yamaguchi, O, Nowotschin, S, Shiraishi, M, Ruchaya, P, Miller, D, Harmer, S, Poliandri, A, Kogaki, S, Sakata, Y, Dunkel, L, Tinker, A, Hadjantonakis, A-K, Sawa, Y, Sasaki, H, Ozono, K, Suzuki, K & Yashiro, K 2016, 'GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway', Cell Reports, vol. 16, no. 4, pp. 1026-1038. https://doi.org/10.1016/j.celrep.2016.06.050

TY - JOUR

T1 - GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

AU - Ishida, Hidekazu

AU - Saba, Rie

AU - Kokkinopoulos, Ioannis

AU - Hashimoto, Masakazu

AU - Yamaguchi, Osamu

AU - Nowotschin, Sonja

AU - Shiraishi, Manabu

AU - Ruchaya, Prashant

AU - Miller, Duncan

AU - Harmer, Stephen

AU - Poliandri, Ariel

AU - Kogaki, Shigetoyo

AU - Sakata, Yasushi

AU - Dunkel, Leo

AU - Tinker, Andrew

AU - Hadjantonakis, Anna-Katerina

AU - Sawa, Yoshiki

AU - Sasaki, Hiroshi

AU - Ozono, Keiichi

AU - Suzuki, Ken

AU - Yashiro, Kenta

PY - 2016/7/26

Y1 - 2016/7/26

N2 - A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

AB - A surface marker that distinctly identifies cardiac progenitors (CPs) is essential for the robust isolation of these cells, circumventing the necessity of genetic modification. Here, we demonstrate that a Glycosylphosphatidylinositol-anchor containing neurotrophic factor receptor, Glial cell line-derived neurotrophic factor receptor alpha 2 (Gfra2), specifically marks CPs. GFRA2 expression facilitates the isolation of CPs by fluorescence activated cell sorting from differentiating mouse and human pluripotent stem cells. Gfra2 mutants reveal an important role for GFRA2 in cardiomyocyte differentiation and development both in vitro and in vivo. Mechanistically, the cardiac GFRA2 signaling pathway is distinct from the canonical pathway dependent on the RET tyrosine kinase and its established ligands. Collectively, our findings establish a platform for investigating the biology of CPs as a foundation for future development of CP transplantation for treating heart failure.

KW - Animals

KW - Cell Differentiation/physiology

KW - Cells, Cultured

KW - Glial Cell Line-Derived Neurotrophic Factor Receptors/metabolism

KW - Glycosylphosphatidylinositols/metabolism

KW - Humans

KW - Ligands

KW - Mice

KW - Myocytes, Cardiac/metabolism

KW - Organogenesis/physiology

KW - Pluripotent Stem Cells/metabolism

KW - Proto-Oncogene Proteins c-ret/metabolism

KW - Receptor Protein-Tyrosine Kinases/metabolism

KW - Signal Transduction/physiology

U2 - 10.1016/j.celrep.2016.06.050

DO - 10.1016/j.celrep.2016.06.050

M3 - Article (Academic Journal)

C2 - 27396331

SN - 2211-1247

VL - 16

SP - 1026

EP - 1038

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

GFRA2 Identifies Cardiac Progenitors and Mediates Cardiomyocyte Differentiation in a RET-Independent Signaling Pathway

Abstract

Bibliographical note

Keywords

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