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Medial HOXA genes demarcate haematopoietic stem cell fate during human development

Pluripotent stem cells (PSC) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into...

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Autores principales: Dou, Diana R., Calvanese, Vincenzo, Sierra, Maria I., Nguyen, Andrew T., Minasian, Arazin, Saarikoski, Pamela, Sasidharan, Rajkumar, Ramirez, Christina M., Zack, Jerome A., Crooks, Gay M., Galic, Zoran, Mikkola, Hanna K.A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981340/
https://www.ncbi.nlm.nih.gov/pubmed/27183470
http://dx.doi.org/10.1038/ncb3354
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author Dou, Diana R.
Calvanese, Vincenzo
Sierra, Maria I.
Nguyen, Andrew T.
Minasian, Arazin
Saarikoski, Pamela
Sasidharan, Rajkumar
Ramirez, Christina M.
Zack, Jerome A.
Crooks, Gay M.
Galic, Zoran
Mikkola, Hanna K.A.
author_facet Dou, Diana R.
Calvanese, Vincenzo
Sierra, Maria I.
Nguyen, Andrew T.
Minasian, Arazin
Saarikoski, Pamela
Sasidharan, Rajkumar
Ramirez, Christina M.
Zack, Jerome A.
Crooks, Gay M.
Galic, Zoran
Mikkola, Hanna K.A.
author_sort Dou, Diana R.
collection PubMed
description Pluripotent stem cells (PSC) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into multipotent haematopoietic cells that had CD34(+)CD38(−/lo)CD90(+)CD45(+)GPI-80(+) foetal liver (FL) HSC immunophenotype, but displayed poor expansion potential and engraftment ability. Transcriptome analysis of immunophenotypic hESC-HSPCs revealed that, despite their molecular resemblance to FL-HSPCs, medial HOXA genes remained suppressed. Knockdown of HOXA7 disrupted FL-HSPC function and caused transcriptome dysregulation that resembled hESC-derived progenitors. Overexpression of medial HOXA genes prolonged FL-HSPC maintenance but was insufficient to confer self-renewal to hESC-HSPCs. Stimulation of retinoic acid signalling during endothelial-to-haematopoietic transition induced the HOXA cluster and other HSC/definitive haemogenic endothelium genes, and prolonged HSPC maintenance in culture. Thus, retinoic acid signalling-induced medial HOXA gene expression marks the establishment of the definitive HSC fate and controls HSC identity and function.
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spelling pubmed-49813402016-11-16 Medial HOXA genes demarcate haematopoietic stem cell fate during human development Dou, Diana R. Calvanese, Vincenzo Sierra, Maria I. Nguyen, Andrew T. Minasian, Arazin Saarikoski, Pamela Sasidharan, Rajkumar Ramirez, Christina M. Zack, Jerome A. Crooks, Gay M. Galic, Zoran Mikkola, Hanna K.A. Nat Cell Biol Article Pluripotent stem cells (PSC) may provide a potential source of haematopoietic stem/progenitor cells (HSPCs) for transplantation; however, unknown molecular barriers prevent the self-renewal of PSC-HSPCs. Using two-step differentiation, human embryonic stem cells (hESCs) differentiated in vitro into multipotent haematopoietic cells that had CD34(+)CD38(−/lo)CD90(+)CD45(+)GPI-80(+) foetal liver (FL) HSC immunophenotype, but displayed poor expansion potential and engraftment ability. Transcriptome analysis of immunophenotypic hESC-HSPCs revealed that, despite their molecular resemblance to FL-HSPCs, medial HOXA genes remained suppressed. Knockdown of HOXA7 disrupted FL-HSPC function and caused transcriptome dysregulation that resembled hESC-derived progenitors. Overexpression of medial HOXA genes prolonged FL-HSPC maintenance but was insufficient to confer self-renewal to hESC-HSPCs. Stimulation of retinoic acid signalling during endothelial-to-haematopoietic transition induced the HOXA cluster and other HSC/definitive haemogenic endothelium genes, and prolonged HSPC maintenance in culture. Thus, retinoic acid signalling-induced medial HOXA gene expression marks the establishment of the definitive HSC fate and controls HSC identity and function. 2016-05-16 2016-06 /pmc/articles/PMC4981340/ /pubmed/27183470 http://dx.doi.org/10.1038/ncb3354 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Dou, Diana R.
Calvanese, Vincenzo
Sierra, Maria I.
Nguyen, Andrew T.
Minasian, Arazin
Saarikoski, Pamela
Sasidharan, Rajkumar
Ramirez, Christina M.
Zack, Jerome A.
Crooks, Gay M.
Galic, Zoran
Mikkola, Hanna K.A.
Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title_full Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title_fullStr Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title_full_unstemmed Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title_short Medial HOXA genes demarcate haematopoietic stem cell fate during human development
title_sort medial hoxa genes demarcate haematopoietic stem cell fate during human development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981340/
https://www.ncbi.nlm.nih.gov/pubmed/27183470
http://dx.doi.org/10.1038/ncb3354
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