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Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells

Lookup NU author(s): Sun Yung, Dr Maria Ledran, Ian Dimmick, Dr Nicholas Slater, Iliana Paraskevopoulou, Dr Mauro Santibanez Koref, Professor Lyle Armstrong, Professor Majlinda LakoORCiD

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Abstract

Understanding the transcriptional cues that direct differentiation of human embryonic stem cells (hESCs) and human-induced pluripotent stem cells to defined and functional cell types is essential for future clinical applications. In this study, we have compared transcriptional profiles of haematopoietic progenitors derived from hESCs at various developmental stages of a feeder-and serum-free differentiation method and show that the largest transcriptional changes occur during the first 4 days of differentiation. Data mining on the basis of molecular function revealed Rho-GTPase signalling as a key regulator of differentiation. Inhibition of this pathway resulted in a significant reduction in the numbers of emerging haematopoietic progenitors throughout the differentiation window, thereby uncovering a previously unappreciated role for Rho-GTPase signalling during human haematopoietic development. Our analysis indicated that SCL was the 11th most upregulated transcript during the first 4 days of the hESC differentiation process. Overexpression of SCL in hESCs promoted differentiation to meso-endodermal lineages, the emergence of haematopoietic and erythro-megakaryocytic progenitors and accelerated erythroid differentiation. Importantly, intrasplenic transplantation of SCL-overexpressing hESC-derived haematopoietic cells enhanced recovery from induced acute anaemia without significant cell engraftment, suggesting a paracrine-mediated effect.

Publication metadata

Author(s): Yung S, Ledran M, Moreno-Gimeno I, Conesa A, Montaner D, Dopazo J, Dimmick I, Slater NJ, Marenah L, Real PJ, Paraskevopoulou I, Bisbal V, Burks D, Santibanez-Koref M, Moreno R, Mountford J, Menendez P, Armstrong L, Lako M

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2011

Volume: 20

Issue: 24

Pages: 4932-4946

Print publication date: 21/09/2011

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/ddr431

DOI: 10.1093/hmg/ddr431

PubMed id: 21937587

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