Wnt-modified materials mediate asymmetric stem cell division to direct human osteogenic tissue formation for bone repair
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Colleges, School and Institutes
The maintenance of human skeletal stem cells (hSSCs) and their progeny in bone defects is a major challenge. Here, we report on a transplantable bandage containing a three-dimensional Wnt-induced osteogenic tissue model (WIOTM). This bandage facilitates the long-term viability of hSSCs (8 weeks) and their progeny, and enables bone repair in an in vivo mouse model of critical-sized calvarial defects. The newly forming bone is structurally comparable to mature cortical bone and consists of human and murine cells. Furthermore, we show that the mechanism of WIOTM formation is governed by Wnt-mediated asymmetric cell division of hSSCs. Covalently immobilizing Wnts onto synthetic materials can polarize single dividing hSSCs, orient the spindle and simultaneously generate a Wnt-proximal hSSC and a differentiation-prone Wnt-distal cell. Our results provide insight into the regulation of human osteogenesis and represent a promising approach to deliver human osteogenic constructs that can survive in vivo and contribute to bone repair.
Funding Information: We thank A. Streit, E. Gentleman, A. Grants and H. Drukmann for discussions about the project. We thank P. Sharpe, T. Desai, N. Ali and M. Tewary for critical reading of the manuscript. We thank C. Healy for his help with µCT imaging. We acknowledge financial support from the Department of Health through the National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre award to the Guy’s & St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and the King’s College Hospital NHS Foundation Trust. K.J.L. and D.H.D. received funding from CAPES, Dental Institute Seed Funding and the BBSRC. This project was supported mainly by a Sir Henry Dale Fellowship (102513/Z/13/Z, S.J.H.). Additional financial support from the UK Regenerative Medicine Platform (MR/R015635/1, S.J.H.) and a London Advanced Therapy Award (S.J.H.) is also acknowledged. Funding Information: S.J.H. conceived the project and designed the experiments. J.R., Y.O., S.S.N., S.J. and S.J.H. performed and analysed the in vitro experiments. Y.O. and D.H.D. performed the in vivo experiments. Y.O. and J.R. analysed the µCT data. J.R., S.S.N. and S.J. performed the histological analysis. J.R. and S.J.H. interpreted the data. A.J.E.H. and K.J.L. commented on the in vivo experiments. J.R., S.J. and S.J.H. prepared the figures. S.J.H. wrote the manuscript. All authors commented on the manuscript. S.J.H. led the project and provided financial support for the project. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
|Number of pages||11|
|Publication status||Published - 21 Sep 2020|