@article {535, title = {Large-scale transcriptional profiling and functional assays reveal important roles for Rho-GTPase signalling and SCL during haematopoietic differentiation of human embryonic stem cells.}, journal = {Hum Mol Genet}, volume = {20}, year = {2011}, month = {2011 Dec 15}, pages = {4932-46}, 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.

}, keywords = {Acute Disease, Anemia, Hemolytic, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Cell Lineage, Cluster Analysis, Embryonic Stem Cells, Erythroid Cells, Flow Cytometry, Gene Expression Profiling, Hematopoietic Stem Cells, Humans, Mice, Myeloid Cells, Paracrine Communication, Proto-Oncogene Proteins, Reverse Transcriptase Polymerase Chain Reaction, rho GTP-Binding Proteins, Signal Transduction, Stem Cell Transplantation, T-Cell Acute Lymphocytic Leukemia Protein 1, Transcriptome}, issn = {1460-2083}, doi = {10.1093/hmg/ddr431}, author = {Yung, Sun and Ledran, Maria and Moreno-Gimeno, Inmaculada and Conesa, Ana and Montaner, David and Dopazo, Joaquin and Dimmick, Ian and Slater, Nicholas J and Marenah, Lamin and Real, Pedro J and Paraskevopoulou, Iliana and Bisbal, Viviana and Burks, Deborah and Santibanez-Koref, Mauro and Moreno, Ruben and Mountford, Joanne and Menendez, Pablo and Armstrong, Lyle and Lako, Majlinda} }