Reciprocal interaction between mesenchymal stem cells and transit amplifying cells regulates tissue homeostasis

Interaction between adult stem cells and their progeny is critical for tissue homeostasis and regeneration. In multiple organs, mesenchymal stem cells (MSCs) give rise to transit amplifying cells (TACs), which then differentiate into different cell types. However, whether and how MSCs interact with TACs remains unknown. Using the adult mouse incisor as a model, we present in vivo evidence that TACs and MSCs have distinct genetic programs and engage in reciprocal signaling cross talk to maintain tissue homeostasis. Specifically, an IGF-WNT signaling cascade is involved in the feedforward from MSCs to TACs. TACs are regulated by tissue-autonomous canonical WNT signaling and can feedback to MSCs and regulate MSC maintenance via Wnt5a/Ror2-mediated non-canonical WNT signaling. Collectively, these findings highlight the importance of coordinated bidirectional signaling interaction between MSCs and TACs in instructing mesenchymal tissue homeostasis, and the mechanisms identified here have important implications for MSC–TAC interaction in other organs.

成体干细胞与其子代细胞之间的相互作用，对于组织稳态与组织再生至关重要。在多个器官中，间充质干细胞（mesenchymal stem cells, MSCs）可分化产生传代扩增细胞（transit amplifying cells, TACs），后者随后进一步分化为多种不同的细胞类型。然而，MSCs是否与TACs发生相互作用，以及其相互作用的具体机制，目前仍未明确。本研究以成年小鼠切牙为实验模型，提供了体内实验证据，证实TACs与MSCs具备独特的遗传程序，并通过双向信号串扰共同维持组织稳态。具体而言，IGF-WNT信号级联参与了MSCs向TACs的前馈信号调控。TACs自身受组织自主性经典Wnt信号通路调控，同时可对MSCs产生反馈调节，通过Wnt5a/Ror2介导的非经典Wnt信号通路维持MSCs的稳态。综上，上述研究结果凸显了MSCs与TACs之间协调的双向信号相互作用，在介导间充质组织稳态维持中的关键作用；本研究揭示的调控机制，对于解析其他器官中MSCs与TACs的相互作用亦具有重要的借鉴意义。