Basis of hematopoietic defects in platelet-derived growth factor (PDGF)-B and PDGF beta-receptor null mice.
Platelet-derived growth factor (PDGF)-B and PDGF beta-receptor (PDGFR beta) deficiency in mice is embryonic lethal and results in cardiovascular, renal, placental, and hematologic disorders. The hematologic disorders are described, and a correlation with hepatic hypocellularity is demonstrated. To explore possible causes, the colony-forming activity of fetal liver cells in vitro was assessed, and hematopoietic chimeras were demonstrated by the transplantation of mutant fetal liver cells into lethally irradiated recipients. It was found that mutant colony formation is equivalent to that of wild-type controls. Hematopoietic chimeras reconstituted with PDGF-B(-/-), PDGFR beta(-/-), or wild-type fetal liver cells show complete engraftment (greater than 98%) with donor granulocytes, monocytes, B cells, and T cells and display none of the cardiovascular or hematologic abnormalities seen in mutants. In mouse embryos, PDGF-B is expressed by vascular endothelial cells and megakaryocytes. After birth, expression is seen in macrophages and neurons. This study demonstrates that hematopoietic PDGF-B or PDGFR beta expression is not required for hematopoiesis or integrity of the cardiovascular system. It is argued that metabolic stress arising from mutant defects in the placenta, heart, or blood vessels may lead to impaired liver growth and decreased production of blood cells. The chimera models in this study will serve as valuable tools to test the role of PDGF in inflammatory and immune responses. (Blood. 2001;97:1990-1998)
Department of Pathology, University of Washington School of Medicine, Seattle, WA 98104-2499, USA.
W E
WE
Kaminski
P
P
Lindahl
N L
NL
Lin
V C
VC
Broudy
J R
JR
Crosby
M
M
Hellström
B
B
Swolin
D F
DF
Bowen-Pope
P J
PJ
Martin
R
R
Ross
C
C
Betsholtz
E W
EW
Raines
D000740:Anemia / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology; D016026:Bone Marrow Transplantation; D005314:Embryonic and Fetal Development / Q000235:genetics; D004899:Erythroblastosis, Fetal / Q000235:genetics / Q000378:metabolism; D005260:Female; D005315:Fetal Diseases / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005318:Fetal Heart / Q000002:abnormalities; D016332:Fetal Tissue Transplantation; D005804:Genes, Lethal; D005816:Genetic Complementation Test; D005838:Genotype; D006410:Hematopoiesis / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D007249:Inflammation; D007668:Kidney / Q000002:abnormalities / Q000196:embryology; D008099:Liver / Q000166:cytology / Q000196:embryology; D008297:Male; D008533:Megakaryocytes / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000235:genetics; D010920:Placenta / Q000503:physiopathology; D011247:Pregnancy; D020574:Proto-Oncogene Proteins c-sis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013312:Stress, Physiological / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D020574:Proto-Oncogene Proteins c-sis; D020797:Receptor, Platelet-Derived Growth Factor beta