Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization During Bone Repair

• Type of Material: Article
• Authors: Jada M. Selma, Georgia Institute of Technology; Anusuya Das, University of Virginia; Anthony O. Awojoodu, Georgia Institute of Technology; Tiffany Wang, Georgia Institute of Technology; Anjan P. Kaushik, University of Virginia; Quanjun Cui, University of Virginia; Hannah Song, Georgia Institute of Technology; Molly E. Ogle, Georgia Institute of Technology; Claire E. Olingy, Georgia Institute of Technology; Emily G. Pendleton, University of Georgia; Kayvan F. Tehrani, University of Georgia; Luke J. Mortensen, University of Georgia; Edward Botchwey, Emory University
• Language: English
• Date: 2018-08-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, Biomedical Engineering Society.
• Final Published Version (URL): http://dx.doi.org/10.1007/s12195-018-0532-0
• Title of Journal or Parent Work: Cellular and Molecular Bioengineering
• ISSN: 1865-5025
• Volume: 11
• Issue: 4
• Start Page: 241
• End Page: 253
• Grant/Funding Information: 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 work was supported by NIH Grants R01AR056445, and R01DE019935 and Department of Defense grant W81XWH-10-1-0928 awarded to Dr. Botchwey.
• Keywords: Cell Biology; MARROW; Bone loss; SPHINGOSINE-1-PHOSPHATE; CRANIAL DEFECT; OSTEOGENESIS IMPERFECTA; Sphingosine 1-phosphate; Sphingolipids; MOUSE MODEL; Technology; HEMATOPOIETIC STEM; Life Sciences & Biomedicine; PROGENITOR CELLS; IN-VIVO; VPC01091; Engineering, Biomedical; STROMAL CELLS; Biophysics; SPHINGOSINE 1-PHOSPHATE; Engineering; Science & Technology; Cell & Tissue Engineering
• Research Categories: Biology, Cell; Engineering, Biomedical; Health Sciences, Medicine and Surgery

Abstract

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.