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First published online June 13, 2005
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2004-0171v1
23/8/1154    most recent
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Submitted on July 20, 2004
Accepted on April 3, 2005

Original Article

Transcriptional profiling of human hematopoiesis during in vitro lineage-specific differentiation

Martina Komor 1, Saskia Güller 1, Claudia D. Baldus 2, Sven de Vos 3, Dieter Hoelzer 1, Oliver G. Ottmann 1, Wolf-Karsten Hofmann 2*

1 Department of Hematology and Oncology, University Hospital, 60590 Frankfurt/Main, Germany
2 Department of Hematology, Oncology and Transfusion Medicine, University Hospital Benjamin Franklin, 12200 Berlin, Germany
3 Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, 90095

* To whom correspondence should be addressed. E-mail: W.K.Hofmann{at}charite.de.


  Abstract

To better understand the transcriptional program that accompanies orderly lineage-specific hematopoietic differentiation, we performed serial oligonucleotide microarray analysis of human normal CD34+ bone marrow cells during lineage-specific differentiation. CD34+ bone marrow cells isolated from healthy individuals were selectively stimulated in vitro with the cytokines EPO, TPO, G- and GM-CSF. Cells from each of the lineages were harvested after 4, 7 and 11 days of culture for expression profiling. Gene expression was analyzed by oligonucleotide microarrays (HG-U133A, Affymetrix, Santa Clara, CA). Experiments were done in triplicates. We identified 258 genes that are consistently up- or down-regulated during the course of lineage-specific differentiation within each specific lineage (horizontal change). In addition, we identified 52 genes that contributed to a specific expression profile, yielding a genetic signature specific for successive stages of differentiation within each of the 3 lineages. Analysis of horizontal changes selected 21 continuously up-regulated genes for EPO-induced differentiation (including GTPase activator proteins RAP1GA1 and ARHGAP8 which regulate small Rho GTPases), 21 for G/GM-CSF-induced differentiation and 91 for TPO-induced differentiation (including DLK1, of which the role in normal hematopoiesis is not defined). During the lineage-specific differentiation, 58 (erythropoiesis), 30 (granulopoiesis) and 37 (thrombopoiesis) genes were significantly down-regulated, respectively. The expression of selected genes was confirmed by real-time PCR. Our data encompass the first extensive transcriptional profile of human hematopoiesis during in vitro lineage-specific differentiation.

Key Words. Gene expression, Hematopoietic development, Hematopoitic stem cell, Mikroarray, Transcription




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