Jada M Selma1,2, Anusuya Das3, Anthony O Awojoodu1,2, Tiffany Wang1,2, Anjan P Kaushik4, Quanjun Cui4, Hannah Song1,2, Molly E Ogle1,2, Claire E Olingy1,2, Emily G Pendleton5, Kayvan F Tehrani5, Luke J Mortensen5,6, Edward A Botchwey1,2. 1. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 315 Ferst Drive Atlanta, Atlanta, GA 30332 USA. 2. Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA 30332 USA. 3. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22903 USA. 4. Department of Orthopedic Surgery, University of Virginia, Charlottesville, VA 22903 USA. 5. Regenerative Bioscience Center, Rhodes Center for ADS, University of Georgia, Athens, GA 30602-2771 USA. 6. School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA 30602-2771 USA.
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 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 hours 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.
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 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 hours 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.
Entities:
Keywords:
Bone loss; Sphingolipids; Sphingosine 1-phosphate; VPC01091
Authors: Takafumi Kimura; Andreas M Boehmler; Gabriele Seitz; Selim Kuçi; Tina Wiesner; Volker Brinkmann; Lothar Kanz; Robert Möhle Journal: Blood Date: 2004-02-26 Impact factor: 22.113