Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells

Abstract Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and obs...

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Autores principales:	Glenn A. MacLean, Jennifer McEldoon, Jialiang Huang, Jeremy Allred, Matthew C. Canver, Stuart. H. Orkin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c790d5a27e354f7cbec740145b8e1ef2
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spelling	oai:doaj.org-article:c790d5a27e354f7cbec740145b8e1ef22021-12-02T15:08:54ZDownregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells10.1038/s41598-018-26123-y2045-2322https://doaj.org/article/c790d5a27e354f7cbec740145b8e1ef22018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-26123-yhttps://doaj.org/toc/2045-2322Abstract Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for endothelin signaling in regulation of B cell development has been identified.Glenn A. MacLeanJennifer McEldoonJialiang HuangJeremy AllredMatthew C. CanverStuart. H. OrkinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Glenn A. MacLean Jennifer McEldoon Jialiang Huang Jeremy Allred Matthew C. Canver Stuart. H. Orkin Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
description	Abstract Individuals with Trisomy 21 (T21) exhibit numerous hematological abnormalities, including reductions in numbers of circulating B and T lymphocytes. To elucidate molecular mechanisms underlying these phenotypes, we differentiated human isogenic disomic and trisomic pluripotent cells, and observed that trisomic cells showed defects in B cell, but not T cell differentiation. Global gene expression of differentiated, trisomic B cells revealed reduced expression of genes encoding endothelin signaling components, namely the Endothelin Receptor B (EDNRB), and its ligand Endothelin1 (EDN1). Depletion of EDNRB mRNA in cord blood-derived CD34+ cells led to defective B cell differentiation, supporting a hypothesis that low EDNRB expression in T21 contributes to intrinsic lymphoid defects. Further evidence for the role of the EDNRB pathway in B cell differentiation was obtained through CRISPR/Cas9 gene targeting in disomic and trisomic iPS cells. Knockout of EDNRB in both cell backgrounds reduced the capacity for B cell differentiation. Collectively, this work identifies downregulation of EDNRB as a causative factor for impaired B lymphocyte generation in trisomic cells, which may contribute to defects in immune function associated with T21. Furthermore, a novel role for endothelin signaling in regulation of B cell development has been identified.
format	article
author	Glenn A. MacLean Jennifer McEldoon Jialiang Huang Jeremy Allred Matthew C. Canver Stuart. H. Orkin
author_facet	Glenn A. MacLean Jennifer McEldoon Jialiang Huang Jeremy Allred Matthew C. Canver Stuart. H. Orkin
author_sort	Glenn A. MacLean
title	Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
title_short	Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
title_full	Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
title_fullStr	Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
title_full_unstemmed	Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells
title_sort	downregulation of endothelin receptor b contributes to defective b cell lymphopoiesis in trisomy 21 pluripotent stem cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/c790d5a27e354f7cbec740145b8e1ef2
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Downregulation of Endothelin Receptor B Contributes to Defective B Cell Lymphopoiesis in Trisomy 21 Pluripotent Stem Cells

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