C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo.
CCAAT enhancer binding protein-alpha (C/EBPalpha) inhibits proliferation in multiple cell types; therefore, we evaluated whether C/EBPalpha-deficient hematopoietic progenitor cells (HPCs) have an increased proliferative potential in vitro and in vivo. In this study we demonstrate that C/EBPalpha(-/-) fetal liver (FL) progenitors are hyperproliferative, show decreased differentiation potential, and show increased self-renewal capacity in response to hematopoietic growth factors (HGFs). There are fewer committed bipotential progenitors in C/EBPalpha(-/-) FL, whereas multipotential progenitors are unaffected. HGF-dependent progenitor cell lines can be derived by directly culturing C/EBPalpha(-/-) FL cells in vitro Hyperproliferative spleen colonies and myelodysplastic syndrome (MDS) are observed in mice reconstituted with C/EBPalpha(-/-) FL cells, indicating progenitor hyperproliferation in vitro and in vivo. C/EBPalpha(-/-) FL lacked macrophage progenitors in vitro and had impaired ability to generate macrophages in vivo. These findings show that C/EBPalpha deficiency results in hyperproliferation of HPCs and a block in the ability of multipotential progenitors to differentiate into bipotential granulocyte/macrophage progenitors and their progeny.
Heath
Victoria
V
Laboratory of Protein Dynamics and Signaling, Science Applications International Corporation-Frederick, Inc, Frederick, MD 20702-1201, USA.
Suh
Hyung Chan
HC
Holman
Matthew
M
Renn
Katie
K
Gooya
John M
JM
Parkin
Sarah
S
Klarmann
Kimberly D
KD
Ortiz
Mariaestela
M
Johnson
Peter
P
Keller
Jonathan
J
D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017690:Cell Transplantation; D002478:Cells, Cultured; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D007377:Interleukin-3 / Q000378:metabolism; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate
D022763:CCAAT-Enhancer-Binding Protein-alpha; D007377:Interleukin-3; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met