Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential.
Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow, self-renewal, proliferation, and differentiation to mature blood cells. Here, we show that loss of p190-B RhoGTPase activating protein, a negative regulator of Rho GTPases, results in enhanced long-term engraftment during serial transplantation. This effect is associated with maintenance of functional HSC-enriched cells. Furthermore, loss of p190-B led to marked improvement of HSC in vivo repopulation capacity during ex vivo culture without altering proliferation and multilineage differentiation of HSC and progeny. Transcriptional analysis revealed that p190-B deficiency represses the up-regulation of p16(Ink4a) in HSCs in primary and secondary transplantation recipients, providing a possible mechanism of p190-B-mediated HSC functions. Our study defines p190-B as a critical transducer element of HSC self-renewal activity and long-term engraftment, thus suggesting that p190-B is a target for HSC-based therapies requiring maintenance of engraftment phenotype.
Xu
Haiming
H
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, Cincinnati, OH 45229, USA.
Eleswarapu
Satyam
S
Geiger
Hartmut
H
Szczur
Kathleen
K
Daria
Deidre
D
Zheng
Yi
Y
Settleman
Jeffrey
J
Srour
Edward F
EF
Williams
David A
DA
Filippi
Marie-Dominique
MD
D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D005434:Flow Cytometry; D020690:GTPase-Activating Proteins / Q000502:physiology*; D006085:Graft Survival; D006410:Hematopoiesis; D019650:Hematopoietic Stem Cell Mobilization; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D008099:Liver / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019172:Transplantation Conditioning
C513042:Arhgap5 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020690:GTPase-Activating Proteins