Coordinate Expansion of Murine Hematopoietic and Mesenchymal Stem Cell Compartments by SHIPi
Abstract
Promoting the expansion of adult stem cell populations offers the potential to ameliorate radiation or chemotherapy-induced bone marrow failure and allows for expedited recovery for patients undergoing these therapies. Previous genetic studies suggested a pivotal role for SH2 domain-containing inositol-5-phosphatase 1 (SHIP1) in limiting the size of the hematopoietic stem cell (HSC) compartment. The aim of this study was to determine whether our recent development of small molecule SHIP1 inhibitors offers the potential for pharmacological expansion of the HSC compartment in vivo. We show here that treatment of mice with aminosteroid inhibitors of SHIP1 (SHIPi) more than doubles the size of the adult mesenchymal stem cell (MSC) compartment while simultaneously expanding the HSC pool sixfold. Consistent with its ability to target SHIP1 function in vivo, SHIPi also significantly increases plasma granulocyte colony-stimulating factor (G-CSF) levels, a growth factor that supports proliferation of HSC. Here, we show that SHIPi-induced G-CSF production mediates HSC and MSC expansion, as in vivo neutralization of G-CSF abrogates the SHIPi-induced expansion of both the HSC and MSC compartments. Due to its expansionary effect on adult stem cell compartments, SHIPi represents a potential novel strategy to improve declining stem cell function in both therapy induced and genetically derived bone marrow failure syndromes.
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3-alpha-Aminocholestane (3AC) is a selective inhibitor of INPP5D.
“Here, we used 3-alpha-Aminocholestane (3AC), a compound previously reported to be a selective inhibitor of INPP5D39, which has been utilized in several studies to reduce INPP5D activity in vivo in mice and in vitro cell culture39–47.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [40]
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PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
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Brooks, R., Fuhler, G. M., Iyer, S., Smith, M. J., Park, M.-Y., Paraiso, K. H. T., Engelman, R. W., & Kerr, W. G. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902844 · Cited by 140 · see citing works
Self-citationCondé, C., Rambout, X., Lebrun, M., Lecat, A., Di Valentin, E., Dequiedt, F., Piette, J., Gloire, G., & Legrand, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041005 · Cited by 33 · see citing works
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The Next Generation of Immunotherapy for Cancer: Small Molecules Could Make Big Waves
Kerr, W. G., & Chisholm, J. D. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1800991 · Cited by 131 · see citing works
Self-citationINPP5D regulates inflammasome activation in human microglia
Chou, V., Pearse, R. V., Aylward, A. J., Ashour, N., Taga, M., Terzioglu, G., Fujita, M., Fancher, S. B., Sigalov, A., Benoit, C. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-42819-w · Cited by 79 · see citing works
Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis
Pedicone, C., Fernandes, S., Dungan, O. M., Dormann, S. M., Viernes, D. R., Adhikari, A. A., Choi, L. B., De Jong, E. P., Chisholm, J. D., & Kerr, W. G. (2020) · Journal of Cell Science · doi:10.1242/jcs.238030 · Cited by 61 · see citing works
Self-citationPedicone, C., Fernandes, S., Matera, A., Meyer, S. T., Loh, S., Ha, J.-H., Bernard, D., Chisholm, J. D., Paolicelli, R. C., & Kerr, W. G. (2022) · iScience · doi:10.1016/j.isci.2022.104170 · Cited by 26 · see citing works
Self-citationINPP5D/SHIP1 regulates inflammasome activation in human microglia
Chou, V., Fancher, S. B., Pearse, R. V., Lee, H., Lam, M., Seyfried, N. T., Bennett, D. A., De Jager, P. L., Menon, V., & Young-Pearse, T. L. (2023) · doi:10.1101/2023.02.25.530025 · Cited by 8 · see citing works
- Authors
- Brooks, R., Iyer, S., Akada, H., Neelam, S., Russo, C. M., Chisholm, J. D., & Kerr, W. G.
- Affiliations
- SUNY Upstate Medical University (US)
- Syracuse University (US)
- Corresponding author
- Kerr, W. G.
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-02-17
- Volume
- 33
- Issue
- 3
- Pages
- 848-858
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1936494662
- Cited by
- 32
- References
- 5
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 5 · 2017: 1 · 2016: 3 · 2015: 3
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Crohn's and Colitis Foundation of America
- Crohn's and Colitis Foundation
- National Institutes of Health (5r01hl107127-04)
- National Heart, Lung, and Blood Institute (R01-HL107127, R01HL085580, R01HL072523)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- hematopoietic stem cells, mesenchymal stem cells, granulocyte colony-stimulating factor, stem cell expansion, bone marrow failure, small molecule inhibitors
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Cell Movement, Hematopoietic Stem Cells, Male, Mice, Inbred C57BL, Phosphoric Monoester Hydrolases, Granulocyte Colony-Stimulating Factor, Mice, Mesenchymal Stem Cells
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