Mesenchymal stem and progenitor cells (MSCs), which normally reside in the bone marrow, are critical to bone health and can be recruited to sites of traumatic bone injury, contributing to new bone formation. The ability to control the trafficking of MSCs provides therapeutic potential for improving traumatic bone healing and therapy for genetic bone diseases such as hypophosphatasia.
In this study, we explored the sphingosine-1-phosphate (S1P) signaling axis as a means to control the mobilization of MSCs into blood and possibly to recruit MSCs for enhancing bone growth.
Loss of S1P receptor 3 (S1PR3) leads to an increase in circulating CD45−/CD29+/CD90+/Sca1+ putative mesenchymal progenitor cells, suggesting that blocking S1PR3 may stimulate MSCs to leave the bone marrow. Antagonism of S1PR3 with the small molecule VPC01091 stimulated acute migration of CD45−/CD29+/CD90+/Sca1+ MSCs into the blood as early as 1.5 h after treatment. VPC01091 administration also increased ectopic bone formation induced by BMP-2 and significantly increased new bone formation in critically sized rat cranial defects, suggesting that mobilized MSCs may home to injuries to contribute to healing. We also explored the possibility of combining S1P manipulation of endogenous host cell occupancy with exogenous MSC transplantation for potential use in combination therapies. Importantly, reducing niche occupancy of host MSCs with VPC01091 does not impede engraftment of exogenous MSCs.
Our studies suggest that MSC mobilization through S1PR3 antagonism is a promising strategy for endogenous tissue engineering and improving MSC delivery to treat bone diseases.
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Mesenchymal stem cell
Sphingosine 1-phosphate receptor
Endothelial progenitor cells
Chemokine receptor 4
Hematopoietic stem and progenitor cell
Stem cell antigen-1
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We would like to thank Kevin Lynch (University of Virginia) for providing VPC01091, Richard Proia (NIH) for providing the S1PR3-/- mice, and the core facilities staff of the Parker H. Petit Institute for Bioengineering and Bioscience for their technical expertise. This work was supported by NIH Grants R01AR056445, and R01DE019935 and Department of Defense grant W81XWH-10-1-0928 awarded to Dr. Botchwey. Our study was also in part supported by the Regenerative Engineering and Medicine Center’s “Georgia Partners in Regenerative Medicine” seed grant and the Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3 M) research grant awarded to Dr. Botchwey and Dr. Mortensen; the Soft Bones Foundation Maher Family Research Grant to Dr. Mortensen; as well as the National Science Foundation grant NSF GRFP DGE-1148903, the NIH/NIGMS Cell and Tissue Engineering Biotechnology training grant T32GM008433, and the Alfred P. Sloan gradate fellowship awarded to Jada Selma.
This study was funded by NIH (Grants# R01AR056445, R01DE019935), Department of Defense (Grant # W81XWH-10-1-0928), Regenerative Engineering and Medicine Center’s “Georgia Partners in Regenerative Medicine” Seed Grant, the Marcus Center for Therapeutic Cell Characterization and Manufacturing Grant, the Soft Bones Foundation Maher Family Research Grant, NSF (Grant# GRFP DGE-1148903), NIH/NIGMS (Grant# T32GM008433) and Alfred P. Sloan Foundation.
Conflict of interest
Ms. Selma declares that she has no conflict of interest. Ms. Wang declares that she has no conflict of interest. Ms. Pendleton declares that she has no conflict of interest. Dr. Botchwey declares that he has no conflict of interest. Dr. Cui has received grants from DOD, NIH, and grants from Exactech (outside the submitted work). Dr. Cui also reports that he is an editorial board member for the Journal of Arthroplasty, Editor-in-Chief for the World Journal of Orthopaedics, and receives royalties from Elsevier. Dr. Das declares that she has no conflict of interest. Dr. Kaushik declares that he has no conflict of interest. Dr. Tehrani declares that he has no conflict of interest. Dr. Mortensen declares that he has no conflict of interest. Dr. Awojoodu declares that he has no conflict of interest. Dr. Song declares that she has no conflict of interest. Dr. Ogle declares that she has no conflict of interest. Dr. Olingy declares that she has no conflict of interest.
No competing financial interests exist.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
Associate Editor Michael R. King oversaw the review of this article.
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Supplementary material 1 (TIFF 49160 kb). Supplemental Fig. 1. Flow cytometry gating for MSCs and LSK cells and S1P receptor expression for MSCs. MSCs are identified in the blood by gating for (A) cells, (B) live cells (C) CD45-/Sca1+cells and finally (D) CD90+/CD29+ cells. (E) Sca1+/CD105+ cells isolated from wild type mice express relatively more S1PR3 compared to whole bone marrow cells. (F) S1PR3-/- mice have more Sca1+/CD105+ cells in circulation (n = 2 mice per group). LSK cells are identified in the blood by gating for (G) cells, (H) single cells, (I) Lineage- cells and (J) Sca1+/C-kit+ cells. Data expressed as mean ± SEM. Abbreviations: WT, wild type; WBM, whole bone marrow
Supplementary material 2 (TIFF 5178 kb). Supplemental Fig. 2. More MSC-like cells migrate to ectopic bone site with systemic VPC01091. Percentage of CD29+/CD90+ cells surrounding ectopic bone site increases with systemic VPC01091 treatment at 1 week (A) and (B) 3 weeks after matrigel + BMP-2 implantation (n = 3 mice per group). Data expressed as mean ± SEM. * p < 0.05. Abbreviations: VPC, VPC01091; mpk, milligram per kilogram
Supplementary material 3 (TIFF 21236 kb). Supplemental Fig. 3. Increase in osteoid body formation and fibroblast-like cell migration to defect site with systemic VPC01091. Representative images of Masson’s trichrome staining of calvarial bone after 8 weeks of saline (A) or 1 mg/kg VPC01091 treatment (C) showing osteoid bodies (red) within the bone (blue). Magnified sections (squared off segments in A, C) of Masson’s trichrome staining of calvarial bone after 8 weeks of saline (B) or 1 mg/kg VPC01091 treatment (D). (E) 3 weeks after treatment, there is an increase in the percentage of CD90+ and CD11b-/CD90+ cells in the defect region (n = 3 mice per group). Data expressed as mean ± SEM. * p < 0.05
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Selma, J.M., Das, A., Awojoodu, A.O. et al. Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization During Bone Repair. Cel. Mol. Bioeng. 11, 241–253 (2018). https://doi.org/10.1007/s12195-018-0532-0
- Sphingosine 1-phosphate
- Bone loss