Granulocyte colony-stimulating factor mobilizes dormant hematopoietic stem cells without proliferation in mice

Abstract

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 CD41 HSC 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.

Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells

“…In addition, the unplanned analyses shown in Figure suggest that G‐CSF may have an ability to rejuvenate DNAm age of HSCs. G‐CSF has a pronounced influence on cellular processes in HSCs and has been shown to selectively mobilize dormant HSCs to the bloodstream in mice (Bernitz, Daniel, Fstkchyan, & Moore, ; Panch, Szymanski, Savani, & Stroncek, ). In our study, these processes could potentially have influenced the DNAm age of the transplanted HSCs or their progeny either directly or through selection by mobilization, and thus selected HSCs with a lower DNAm age.…”

Arachidonic acid and Docosahexanoic acid enhance platelet formation from human apheresis-derived CD34+ cells

“…45 According to the recent finding by Bernitz et al (Accepted February 6, 2017, Blood 2017: blood-2016-11-752923;doi:https://doi.org/ 10.1182/blood-2016-11-752923) mobilized PB has surpassed harvested BM as a source of HSCs for clinical transplantation. 46 G-CSF mobilizes dormant haematopoietic stem cells from bone marrow to peripheral blood without proliferation. G-CSF treatment does not induce detectable engraftment of CD41 high cells from bone marrow compartment limiting their regenerative properties.…”

Myelopoiesis of the Amphibian Xenopus laevis Is Segregated to the Bone Marrow, Away From Their Hematopoietic Peripheral Liver

“…In turn, during monopoiesis csf1r gene expression increases with myeloid lineage commitment (58,59). Conversely, in addition to myeloid-lineage cells, csf3r (granulocyte colony-stimulating factor receptor, gcsf ) is also expressed by mammalian HSCs, which facilitates CSF-3 (granulocyte colony stimulating factor, G-CSF)-mediated mobilization of HSCs out of the mammalian bone marrow into circulation (60,61). Notably and compared to total LP cells, the rCXCL12-recruited LP cells possessed lower expression of csf1r but greater mRNA levels of csf3r.…”