National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing, 102206, China.
Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, 102206, China.
Nat Commun. 2024 Mar 26;15(1):2656. doi: 10.1038/s41467-024-46956-8.
The manipulation of cell identity by reprograming holds immense potential in regenerative medicine, but is often limited by the inefficient acquisition of fully functional cells. This problem can potentially be resolved by better understanding the reprogramming process using in vivo genetic models, which are currently scarce. Here we report that both enterocytes (ECs) and enteroendocrine cells (EEs) in adult Drosophila midgut show a surprising degree of cell plasticity. Depleting the transcription factor Tramtrack in the differentiated ECs can initiate Prospero-mediated cell transdifferentiation, leading to EE-like cells. On the other hand, depletion of Prospero in the differentiated EEs can lead to the loss of EE-specific transcription programs and the gain of intestinal progenitor cell identity, allowing cell cycle re-entry or differentiation into ECs. We find that intestinal progenitor cells, ECs, and EEs have a similar chromatin accessibility profile, supporting the concept that cell plasticity is enabled by pre-existing chromatin accessibility with switchable transcription programs. Further genetic analysis with this system reveals that the NuRD chromatin remodeling complex, cell lineage confliction, and age act as barriers to EC-to-EE transdifferentiation. The establishment of this genetically tractable in vivo model should facilitate mechanistic investigation of cell plasticity at the molecular and genetic level.
通过重编程来操纵细胞特性在再生医学中具有巨大的潜力，但通常受到完全功能性细胞获取效率低下的限制。通过使用体内遗传模型更好地了解重编程过程，这个问题可能会得到解决，但目前这种模型非常稀缺。在这里，我们报告成年果蝇中肠的肠细胞（ECs）和肠内分泌细胞（EEs）表现出惊人的细胞可塑性。在分化的 ECs 中耗尽转录因子 Tramtrack 可以启动 Prospero 介导的细胞转分化，导致 EE 样细胞。另一方面，在分化的 EEs 中耗尽 Prospero 会导致 EE 特异性转录程序的丧失和肠祖细胞身份的获得，从而允许细胞周期重新进入或分化为 ECs。我们发现肠祖细胞、ECs 和 EEs 具有相似的染色质可及性谱，支持细胞可塑性是由预先存在的具有可切换转录程序的染色质可及性所实现的概念。通过该系统进行的进一步遗传分析表明，NuRD 染色质重塑复合物、细胞谱系冲突和年龄是 EC 到 EE 转分化的障碍。该遗传上易于处理的体内模型的建立应该有助于在分子和遗传水平上对细胞可塑性进行机制研究。
