Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect.
The regulation of HSC proliferation and engraftment of the BM is an important but poorly understood process, particularly during ontogeny. Here we show that in mice, all HSCs are cycling until 3 weeks after birth. Then, within 1 week, most became quiescent. Prior to 4 weeks of age, the proliferating HSCs with long-term multilineage repopulating activity displayed an engraftment defect when transiting S/G2/M. During these cell cycle phases, their expression of CXC chemokine ligand 12 (CXCL12; also referred to as stromal cell-derived factor 1 [SDF-1]) transiently increased. The defective engrafting activity of HSCs in S/G2/M was reversed when cells were allowed to progress into G1 prior to injection or when the hosts (but not the cells) were pretreated with a CXCL12 antagonist. Interestingly, the enhancing effect of CXCL12 antagonist pretreatment was exclusive to transplants of long-term multilineage repopulating HSCs in S/G2/M. These results demonstrate what we believe to be a new HSC regulatory checkpoint during development. They also suggest an ability of HSCs to express CXCL12 in a fashion that changes with cell cycle progression and is associated with a defective engraftment that can be overcome by in vivo administration of a CXCL12 antagonist.
Bowie
Michelle B
MB
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
McKnight
Kristen D
KD
Kent
David G
DG
McCaffrey
Lindsay
L
Hoodless
Pamela A
PA
Eaves
Connie J
CJ
D000818:Animals; D000831:Animals, Newborn; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006413:Hematopoietic System / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D018960:Hyaluronan Receptors / Q000235:genetics; D039441:Integrin alpha4 / Q000235:genetics; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics; D013936:Thymidine / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D018960:Hyaluronan Receptors; D019718:Receptors, CXCR4; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D019009:Proto-Oncogene Proteins c-kit; D005472:Fluorouracil; D013936:Thymidine