Granulocyte-colony stimulating factor impedes recovery from damage caused by cytotoxic agents through increased differentiation at the expense of self-renewal.
Abstract
G-CSF is routinely used to hasten recovery from chemotherapy-induced neutropenia. We have recently shown that G-CSF, when combined with stem cell-damaging cytotoxic agents, results in enhanced stem cell damage and loss of marrow reserve. To investigate the mechanisms of stem cell damage caused by G-CSF, we gave C57BL/6 (B6) mice repeated doses of cyclophosphamide ([CY] 84 mg/kg) or carmustine ([BCNU] 13.2 mg/kg) and G-CSF (250 microg/kg/day) for either four days or eight days. Two different regimens of G-CSF were chosen to study the influence of increased proliferation on hematopoiesis which was measured at the end of the first, third and sixth 14-day cycle of each cytotoxic agent and 7 and 20 weeks after completion of all cycles. A spectrum of hematopoietic indices was measured including WBC, bone marrow cellularity, granulocyte/macrophage-colony-forming cells (GM-CFC), colony-forming cells with high proliferative-potential (HPP-CFC), cobblestone area-forming cells ([CAFC]-day 7 and CAFC-day 28), and long-term marrow repopulating ability in vivo. Despite the absence of differences in peripheral blood cell counts or bone marrow cellularity 14 days after each dose, progenitor cell levels (HPP-CFC, GM-CFC, and CAFC-7) were increased up to 2.5-fold with cytotoxic agent and G-CSF administration compared with cytotoxic agent administration alone. Mice given G-CSF for eight days had the greatest number of progenitors suggesting a dose-response relationship for G-CSF administration. G-CSF resulted in a decrease in hematopoietic stem cell (CAFC-28) content when measured two weeks after each cycle of saline, CY, and BCNU. Twenty weeks after six cycles of BCNU, the reduction in stem cell levels persisted and was further decreased when G-CSF was added to BCNU for four or eight days. Data from this study suggest that the most likely explanation for the damaging effects of G-CSF is that G-CSF directly or indirectly induces stem cells to differentiate into more committed hematopoietic cells resulting in a loss of marrow reserve. This effect is enhanced in animals with an already compromised hematopoietic stem cell compartment as seen with repeated doses of BCNU.
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The use of HGFs may worsen IR-induced residual BM damage by promoting proliferation and differentiation of HSCs and HPCs at the expense of HSC self-renewal.
“In fact, the use of HGFs may worsen IR-induced residual BM damage by promoting proliferation and differentiation of HSCs and HPCs at the expense of HSC self-renewal.6”
From Total body irradiation causes long-term mouse BM injury via induction of HSC premature senescence in an Ink4a- and Arf-independent manner (2014) · cites this paper as [6]
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- Authors
- van Os, R., Robinson, S., Sheridan, T., & Mauch, P. M.
- Affiliations
- Department of Radiation Oncology, Brigham and Women's Hospital and the Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachustetts, USA
- Brigham and Women's Hospital (US)
- ORCID
- Mauch, Peter M.
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-03
- Volume
- 18
- Issue
- 2
- Pages
- 120-127
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W2157990290
- Cited by
- 57
- References
- 32
- Citations by year
- 2025: 1 · 2024: 8 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 3 · 2017: 1 · 2016: 5 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 4
- FWCI
- 1.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01-CA 10941-28, R01CA010941)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Health Sciences › Medicine › Oncology › Neutropenia and Cancer Infections
- Keywords
- granulocyte colony-stimulating factor, hematopoietic stem cells, hematopoietic progenitor cells, cyclophosphamide, BCNU, chemotherapy-induced neutropenia, stem cell differentiation, self-renewal, hematopoietic recovery, cobblestone area-forming cells
- MeSH terms
- Animals, Carmustine, Cell Differentiation, Cyclophosphamide, Hematopoietic Stem Cells, Mice, Inbred C57BL, Granulocyte Colony-Stimulating Factor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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