Granulocyte colony-stimulating factor mobilizes dormant hematopoietic stem cells without proliferation in mice.
Granulocyte colony-stimulating factor (G-CSF) is used clinically to treat leukopenia and to enforce hematopoietic stem cell (HSC) mobilization to the peripheral blood (PB). However, G-CSF is also produced in response to infection, and excessive exposure reduces HSC repopulation capacity. Previous work has shown that dormant HSCs contain all the long-term repopulation potential in the bone marrow (BM), and that as HSCs accumulate a divisional history, they progressively lose regenerative potential. As G-CSF treatment also induces HSC proliferation, we sought to examine whether G-CSF-mediated repopulation defects are a result of increased proliferative history. To do so, we used an established H2BGFP label retaining system to track HSC divisions in response to G-CSF. Our results show that dormant HSCs are preferentially mobilized to the PB on G-CSF treatment. We find that this mobilization does not result in H2BGFP label dilution of dormant HSCs, suggesting that G-CSF does not stimulate dormant HSC proliferation. Instead, we find that proliferation within the HSC compartment is restricted to CD41-expressing cells that function with short-term, and primarily myeloid, regenerative potential. Finally, we show CD41 expression is up-regulated within the BM HSC compartment in response to G-CSF treatment. This emergent CD41HiHSC fraction demonstrates no observable engraftment potential, but directly matures into megakaryocytes when placed in culture. Together, our results demonstrate that dormant HSCs mobilize in response to G-CSF treatment without dividing, and that G-CSF-mediated proliferation is restricted to cells with limited regenerative potential found within the HSC compartment.
Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, and The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Jeffrey M
JM
Bernitz
Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, and The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Michael G
MG
Daniel
Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, and The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Yesai S
YS
Fstkchyan
Department of Cell, Developmental and Regenerative Biology, Black Family Stem Cell Institute, and The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY.
Kateri
K
Moore
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D040201:Platelet Membrane Glycoprotein IIb / Q000096:biosynthesis* / Q000235:genetics
D040201:Platelet Membrane Glycoprotein IIb; D016179:Granulocyte Colony-Stimulating Factor