Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix
Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix
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通过脱细胞基质中恢复的关键信号实现牙齿器官的实质和基质组织再生
DOI：
10.1038/s41563-019-0368-6
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发表时间：
2019-06-01
期刊：
影响因子：
41.2
通讯作者：
Mao, Jeremy
中科院分区：
文献类型：
--
作者：
He, Ling;Zhou, Jian;Mao, Jeremy
移植细胞可再生器官的实质细胞，但移植的实质细胞如何诱导间质再生尚不清楚。尽管通常使用脱细胞基质，但对于组织或器官再生必须恢复的关键信号知之甚少。我们报道了一个重要的发育基因Alx3，通过直接激活Wnt3a和血管内皮生长因子来协调成人实质和间质再生。与原生成人祖细胞形成的适度实质相反，脱细胞支架中的alx3修复细胞不仅产生血管化基质，参与血管内皮生长因子信号传导，还通过Wnt/ β -catenin途径产生实质牙本质。在原位大型动物模型中，在软组织和间质消融后，wnt3a招募的内源性细胞再生神经血管间质并分化为实质成牙细胞样细胞，并将这一过程扩展为新形成的牙本质，其结构-力学等效于天然牙本质。因此，Alx3-Wnt3a轴使先天具有适度再生能力的出生后祖细胞能够再生成体组织。去细胞基质中被耗尽的信号可能被发育关键基因或相应的蛋白恢复。
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/beta-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.