Division of Developmental Biology and Regenerative Medicine, Department of Anatomy, Iwate Medical University, 1-1-1, Idaidori, Yahaba, Iwate 028-3694, Japan.
Division of Anatomy and Cell Biology of the Hard Tissue, Department of Tissue Regeneration and Reconstruction, Niigata University Graduate School of Medical and Dental Sciences, 2-5274 Gakkocho-dori, Chuo-ku, Niigata 951-8514, Japan.
Development. 2021 Feb 15;148(4):dev194787. doi: 10.1242/dev.194787.
Stem cells are maintained in specific niches that strictly regulate their proliferation and differentiation for proper tissue regeneration and renewal. Molecular oxygen (O) is an important component of the niche microenvironment, but little is known about how O governs epithelial stem cell (ESC) behavior. Here, we demonstrate that O plays a crucial role in regulating the proliferation of ESCs using the continuously growing mouse incisors. We have revealed that slow-cycling cells in the niche are maintained under relatively hypoxic conditions compared with actively proliferating cells, based on the blood vessel distribution and metabolic status. Mechanistically, we have demonstrated that, during hypoxia, HIF1α upregulation activates the RhoA signal, thereby promoting cortical actomyosin and stabilizing the adherens junction complex, including merlin. This leads to the cytoplasmic retention of YAP/TAZ to attenuate cell proliferation. These results shed light on the biological significance of blood-vessel geometry and the signaling mechanism through microenvironmental O to orchestrate ESC behavior, providing a novel molecular basis for the microenvironmental O-mediated stem cell regulation during tissue development and renewal.
干细胞存在于特定的龛位中，这些龛位严格调控着干细胞的增殖和分化，以实现组织的再生和更新。分子氧（O）是微环境龛位的重要组成部分，但目前对于 O 如何调控上皮干细胞（ESC）行为知之甚少。在这里，我们利用不断生长的小鼠切牙证明了 O 在调节 ESC 增殖方面发挥着关键作用。我们揭示了，与活跃增殖的细胞相比，龛位中的慢周期细胞处于相对低氧的环境中，这是基于血管分布和代谢状态得出的结论。从机制上讲，我们已经证明，在低氧条件下，HIF1α 的上调激活了 RhoA 信号，从而促进了皮质肌动球蛋白的形成，并稳定了黏着连接复合体，包括 Merlin。这导致 YAP/TAZ 滞留在细胞质中，从而抑制细胞增殖。这些结果揭示了血管几何形状的生物学意义以及通过微环境 O 传递信号的机制，以协调 ESC 行为，为组织发育和更新过程中微环境 O 介导的干细胞调控提供了新的分子基础。
