2025-11-18 東京大学
図1:c1qtnf3をノックダウンすると尾再生が阻害される
ツメガエル幼生は(上図)通常であれば尾を点線の位置で切断しても1週間程度で機能的な尾を再生するが、(下図)c1qtnf3ノックダウン操作を行うと十分な尾再生ができなくなる。両矢印は再生尾の長さ、青線は尾の輪郭を示している。(Kato et al., PNAS, 2025より改変して転載)
<関連情報>
推定筋幹細胞はc1qtnf3を介してマクロファージ機能を変化させ、アフリカツメガエルの尾の再生を促進する Putative muscle stem cells promote Xenopus tail regeneration by modifying macrophage function via c1qtnf3
Sumika Kato, Takeo Kubo, and Taro Fukazawa
Proceedings of the National Academy of Sciences
DOI:https://doi.org/10.1073/pnas.2504410122
Significance
Using single-cell analysis, we investigated tissue stem cell dynamics to elucidate a molecular mechanism of Xenopus tadpole tail regeneration. We found that presumptive muscle stem cells promote tail regeneration by expressing c1q tumor necrosis factor-related protein 3 (c1qtnf3), which acts to switch the macrophage mode of function to a regeneration-promoting state. Our findings provide clues to the molecular mechanisms of tail regeneration in which tissue stem cells indirectly promote tissue regeneration by modulating immune responses. Understanding such stem cell–immune cell interactions in highly regenerative organisms is an important step toward elucidating the fundamental principles of tissue regeneration across vertebrate species.
Abstract
In Xenopus laevis tadpole tail regeneration, lineage-restricted tissue stem cells produce differentiated cells that form regenerated tail tissues, but the behavioral dynamics of tissue stem cells during tail regeneration remain largely unknown. We previously reported that multiple tissue stem/progenitor cells can be efficiently enriched from regeneration buds using the side population (SP) method. Here, we performed trajectory inference using single-cell RNA sequencing data of the SP fraction to construct differentiation trajectories and identify putative tissue stem cell populations that initiate differentiation pathways. We found that complement c1q tumor necrosis factor-related protein 3 (c1qtnf3) is specifically expressed in putative muscle stem cells (MSC) and, using knockdown (KD; CRISPR/Cas9-based F0 crispants) experiments, demonstrated that c1qtnf3 is necessary for tail regeneration. Furthermore, we found that the impaired tail regeneration by c1qtnf3 KD was accompanied by abrogation of macrophage-like cell accumulation at the amputation site. These phenotypes were rescued by macrophage-like cell-specific forced expression of neutrophil cytosolic factor 1, a gene related to effector molecule production in myeloid cells, suggesting that the impaired tail regeneration by c1qtnf3 KD is due to macrophage dysregulation. Our findings suggest that, in Xenopus, putative MSC modulate macrophage function via c1qtnf3 expression for successful tail regeneration.
