Qin Liangshan, Zhang Dandan, Liu Siyi, Liu Quanhui, Liu Mingxing, Huang Ben
College of Animal Science and Technology, Guangxi University, Nanning, China.
Guangxi Academy of Medical Sciences, Nanning, China.
Front Cell Dev Biol. 2023 Aug 2;11:1194070. doi: 10.3389/fcell.2023.1194070. eCollection 2023.
The plasticity of cell identity allows cellular reprogramming that manipulates the lineage of cells to generate the target cell types, bringing new avenues for disease modeling and autologous tailored cell therapy. Previously, we had already successfully established a technical platform for inducing fibroblast reprogramming to chemically induced mammary epithelial cells (CiMECs) by small-molecule compounds. However, exactly how the molecular mechanism driving the lineage conversion remains unknown. We employ the RNA-sequencing technology to investigate the transcriptome event during the reprogramming process and reveal the molecular mechanisms for the fate acquisition of mammary lineage. The multi-step reprogramming process first overcomes multiple barriers, including the inhibition of mesenchymal characteristics, pro-inflammatory and cell death signals, and then enters an intermediate plastic state. Subsequently, the hormone and mammary development genes were rapidly activated, leading to the acquisition of the mammary program together with upregulation of the milk protein synthesis signal. Moreover, the gene network analyses reveal the potential relationship between the TGF-β signaling pathway to mammary lineage activation, and the changes in the expression of these genes may play important roles in coordinating the reprogramming process. Together, these findings provide critical insights into the molecular route and mechanism triggered by small-molecule compounds that induce fibroblast reprogramming into the fate of mammary epithelial cells, and they also laid a foundation for the subsequent research on the development and differentiation of mammary epithelial cells and lactation.
细胞身份的可塑性允许细胞重编程，即操纵细胞谱系以生成目标细胞类型，为疾病建模和自体定制细胞治疗带来了新途径。此前，我们已经成功建立了一个技术平台，通过小分子化合物诱导成纤维细胞重编程为化学诱导的乳腺上皮细胞（CiMECs）。然而，驱动谱系转换的分子机制究竟如何仍不清楚。我们采用RNA测序技术来研究重编程过程中的转录组事件，并揭示乳腺谱系命运获得的分子机制。多步骤重编程过程首先克服多个障碍，包括抑制间充质特征、促炎和细胞死亡信号，然后进入中间可塑性状态。随后，激素和乳腺发育基因被迅速激活，导致乳腺程序的获得以及乳蛋白合成信号的上调。此外，基因网络分析揭示了TGF-β信号通路与乳腺谱系激活之间的潜在关系，这些基因表达的变化可能在协调重编程过程中发挥重要作用。总之，这些发现为小分子化合物诱导成纤维细胞重编程为乳腺上皮细胞命运所触发的分子途径和机制提供了关键见解，也为后续乳腺上皮细胞发育、分化和泌乳的研究奠定了基础。
