Cells are transplanted to regenerate an organs’ parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/β–catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure–mechanical equivalency to native dentin. Thus, the Alx3–Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.
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Data supporting the findings of this study are available within the article and from the corresponding authors upon reasonable request.
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We thank Q. Guo, P. Ralph-Birkett and Y. Tse for administrative and technical assistance. We thank F. Meijlink and J. Deschamps for gifts of Alx3 fragment plasmid, M. S. Shelanski for suggestions for two antibodies, J. E. Nör for sharing his insight on VEGF signalling, Y. Zhang for technical help with the Wnt3a luciferase promoter constructs and A. F. Fouad for citation of the Survey of Dental Services Rendered. The work is supported by NIH grants R01DE025643, R01DE023112, R01AR065023, R01DE025969 and R01DE026297, and an Osteo Science Foundation grant to J. J. Mao. The scholarly effort of several co-authors was supported by National Natural Science Foundation of China grants 81570939 and 81741106 and the Beijing Municipal Administration of Hospitals’ Youth Programme (QML20161503 to J.Zhou), National Natural Science Foundation of China grants 81271110 to Z.W., 81170932 to J.L., 81371136 to X.Z., National Science and Technology Support Program 2014DFA31990 to Z.W. and Program of International Science and Technology Cooperation 2014DFA31990 to L.Y.
J.J.M. has co-founded Innovative Elements and Xinkewo with the goal to develop regenerative products. The other authors declare no competing interests in this article.
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He, L., Zhou, J., Chen, M. et al. Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix. Nat. Mater. 18, 627–637 (2019). https://doi.org/10.1038/s41563-019-0368-6
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