Abstract
The specialized microenvironment or niche where stem cells reside provides regulatory input governing stem cell function. We tested the hypothesis that targeting the niche might improve stem cell–based therapies using three mouse models that are relevant to clinical uses of hematopoietic stem (HS) cells. We and others previously identified the osteoblast as a component of the adult HS cell niche and established that activation of the parathyroid hormone (PTH) receptor on osteoblasts increases stem cell number1,2,3. Here we show that pharmacologic use of PTH increases the number of HS cells mobilized into the peripheral blood for stem cell harvests, protects stem cells from repeated exposure to cytotoxic chemotherapy and expands stem cells in transplant recipients. These data provide evidence that the niche may be an attractive target for drug-based stem cell therapeutics.
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Acknowledgements
The authors would like to thank the Cheryl Chagnon Lymphoma Research Fund for their generous support. Financial support for this work was also provided by the Burroughs Wellcome Fund, Doris Duke Charitable Trust (D.T.S.) and the National Institutes of Health (G.B.A., H.M.K., D.T.S.).
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G.B.A., K.S.C., L.M.C., H.M.K. and D.T.S. designed the experiments. G.B.A., R.P.M., I.R.A. and K.T.C. performed the experiments. G.B.A., R.P.M., I.R.A., K.T.C., K.S.C., L.M.C., H.M.K. and D.T.S. analyzed the data obtained. G.B.A. and D.T.S. drafted the manuscript. G.B.A., R.P.M., I.R.A., K.T.C., K.S.C., L.M.C., H.M.K. and D.T.S. provided revisions to the manuscript.
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A patent has been filed related to this work and D.T.S. is a founder of a company that has licensed the patent.
Supplementary information
Supplementary Fig. 1
Purified primitive hematopoietic cells do not express PTH Receptor 1. (PDF 157 kb)
Supplementary Fig. 2
Complete blood count analysis of the peripheral blood of mice treated with PTH or control (saline) for 5 weeks followed by 5 days G-CSF mobilization or control. (PDF 245 kb)
Supplementary Fig. 3
Complete blood count analysis of the peripheral blood of mice treated with PTH, G-CSF, PTH plus G-CSF or control (saline) during the four cycles of chemotherapy. (PDF 271 kb)
Supplementary Fig. 4
Complete blood count analysis of the peripheral blood of mice treated with PTH or control (saline) during the six-week treatment period of the primary recipients. (PDF 207 kb)
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Adams, G., Martin, R., Alley, I. et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol 25, 238–243 (2007). https://doi.org/10.1038/nbt1281
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DOI: https://doi.org/10.1038/nbt1281
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