Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8575, Japan.
Regenerative Medicine Division, Analytical Research Department, Technology Development Unit, Life Science Institute, Inc., Tokyo, Japan.
Cell Mol Life Sci. 2022 Oct 6;79(11):542. doi: 10.1007/s00018-022-04555-0.
Stem cells undergo cytokine-driven differentiation, but this process often takes longer than several weeks to complete. A novel mechanism for somatic stem cell differentiation via phagocytosing 'model cells' (apoptotic differentiated cells) was found to require only a short time frame. Pluripotent-like Muse cells, multipotent mesenchymal stem cells (MSCs), and neural stem cells (NSCs) phagocytosed apoptotic differentiated cells via different phagocytic receptor subsets than macrophages. The phagocytosed-differentiated cell-derived contents (e.g., transcription factors) were quickly released into the cytoplasm, translocated into the nucleus, and bound to promoter regions of the stem cell genomes. Within 24 ~ 36 h, the cells expressed lineage-specific markers corresponding to the phagocytosed-differentiated cells, both in vitro and in vivo. At 1 week, the gene expression profiles were similar to those of the authentic differentiated cells and expressed functional markers. Differentiation was limited to the inherent potential of each cell line: triploblastic-, adipogenic-/chondrogenic-, and neural-lineages in Muse cells, MSCs, and NSCs, respectively. Disruption of phagocytosis, either by phagocytic receptor inhibition via small interfering RNA or annexin V treatment, impeded differentiation in vitro and in vivo. Together, our findings uncovered a simple mechanism by which differentiation-directing factors are directly transferred to somatic stem cells by phagocytosing apoptotic differentiated cells to trigger their rapid differentiation into the target cell lineage.
干细胞经历细胞因子驱动的分化，但这个过程通常需要数周时间才能完成。我们发现了一种通过吞噬“模型细胞”（凋亡分化细胞）使体干细胞分化的新机制，它只需要很短的时间框架。多能样 Muse 细胞、多能间充质干细胞 (MSCs) 和神经干细胞 (NSCs) 通过不同于巨噬细胞的不同吞噬受体亚群吞噬凋亡分化细胞。吞噬的分化细胞来源的内容（例如，转录因子）被迅速释放到细胞质中，易位到细胞核中，并与干细胞基因组的启动子区域结合。在 24 到 36 小时内，这些细胞在体外和体内表达与吞噬的分化细胞相对应的谱系特异性标记。在 1 周时，基因表达谱与真实分化细胞相似，并表达功能性标记。分化仅限于每条细胞系的固有潜能：三胚层、脂肪/软骨谱系和神经谱系，分别在 Muse 细胞、MSCs 和 NSCs 中。吞噬作用的中断，无论是通过小干扰 RNA 抑制吞噬受体还是用 Annexin V 处理，都阻止了体外和体内的分化。总之，我们的研究结果揭示了一种简单的机制，即通过吞噬凋亡分化细胞将分化指导因子直接转移到体干细胞中，从而触发它们快速分化为目标细胞谱系。
