Lineage-instructive function of C/EBPα in multipotent hematopoietic cells and early thymic progenitors.
Hematopoiesis is tightly controlled by transcription regulatory networks, but how and when specific transcription factors control lineage commitment are still largely unknown. Within the hematopoietic stem cell (Lin(-)Sca-1(+)c-Kit(+)) compartment these lineage-specific transcription factors are expressed at low levels but are up-regulated with the process of lineage specification. CCAAT/enhancer binding protein α (C/EBPα) represents one of these factors and is involved in myeloid development and indispensable for formation of granulocytes. To track the cellular fate of stem and progenitor cells, which express C/EBPα, we developed a mouse model expressing Cre recombinase from the Cebpa promoter and a conditional EYFP allele. We show that Cebpa/EYFP(+) cells represent a significant subset of multipotent hematopoietic progenitors, which predominantly give rise to myeloid cells in steady-state hematopoiesis. C/EBPα induced a strong myeloid gene expression signature and down-regulated E2A-induced regulators of early lymphoid development. In addition, Cebpa/EYFP(+) cells compose a fraction of early thymic progenitors with robust myeloid potential. However, Cebpa/EYFP(+) multipotent hematopoietic progenitors and early thymic progenitors retained the ability to develop into erythroid and T-lymphoid lineages, respectively. These findings support an instructive but argue against a lineage-restrictive role of C/EBPα in multipotent hematopoietic and thymic progenitors.
Wölfler
Albert
A
Department of Hematology, Erasmus Medical Center, Rotterdam, The Netherlands.
Danen-van Oorschot
Astrid A
AA
Haanstra
Jurgen R
JR
Valkhof
Marijke
M
Bodner
Claudia
C
Vroegindeweij
Eric
E
van Strien
Paulette
P
Novak
Alexandra
A
Cupedo
Tom
T
Touw
Ivo P
IP
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002451:Cell Compartmentation; D019070:Cell Lineage; D049109:Cell Proliferation; D003114:Colony-Forming Units Assay; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*
D001426:Bacterial Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D008164:Luminescent Proteins; D012333:RNA, Messenger; C054562:yellow fluorescent protein, Bacteria; C045073:Cre recombinase; D019426:Integrases