Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix

Ling He, Jian Zhou, Mo Chen, Chyuan Sheng Lin, Sahng G. Kim, Yue Zhou, Lusai Xiang, Ming Xie, Hanying Bai, Hai Yao, Changcheng Shi, Paulo G. Coelho, Timothy G. Bromage, Bin Hu, Nick Tovar, Lukasz Witek, Jiaqian Wu, Kenian Chen, Wei Gu, Jinxuan ZhengTzong Jen Sheu, Juan Zhong, Jin Wen, Yuting Niu, Bin Cheng, Qimei Gong, David M. Owens, Milda Stanislauskas, Jasmine Pei, Gregory Chotkowski, Sainan Wang, Guodong Yang, David J. Zegarelli, Xin Shi, Myron Finkel, Wen Zhang, Junyuan Li, Jiayi Cheng, Dennis P. Tarnow, Xuedong Zhou, Zuolin Wang, Xinquan Jiang, Alexander Romanov, David W. Rowe, Songlin Wang, Ling Ye, Junqi Ling, Jeremy Mao

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)627-637
Number of pages11
JournalNature Materials
Issue number6
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • General Chemistry
  • General Materials Science
  • Condensed Matter Physics
  • Mechanics of Materials
  • Mechanical Engineering


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