以色列魏茨曼科学研究所Uri Alon等研究人员合作揭示大肠杆菌中一条抑制突变体控制的合成分化回路。这一研究成果于2024年2月5日在线发表在学术期刊《细胞》上。
研究人员通过在大肠杆菌中设计一种合成分化回路，展示了一种解决方案。该分化回路能产生可调的干细胞、祖细胞和分化细胞的合成类似物。它通过将分化与一种必需酶的产生结合起来，从而使非分化突变体处于不利地位，从而抵御突变。在长期沿海过程中，该回路选择并维持了正分化率。
令人惊讶的是，在生长条件发生巨大变化的情况下，这种分化率仍然保持不变。研究人员发现，中转扩增细胞（快速生长的祖细胞）是这种环境稳健性的基础。这些研究结果让人们深入了解了分化的稳定性，并为演化稳定的多细胞联合体的工程设计提供了一种强有力的方法。
据了解，分化对多细胞性至关重要。然而，它本身也容易受到无法分化的突变细胞的影响。这些突变体通过过度自我更新来取代正常细胞。目前还不清楚有什么机制可以抵制这种突变体的扩张。
附：英文原文
Title: A synthetic differentiation circuit in Escherichia coli for suppressing mutant takeover
Author: David S. Glass, Anat Bren, Elizabeth Vaisbourd, Avi Mayo, Uri Alon
Issue&Volume: 2024-02-05
Abstract: Differentiation is crucial for multicellularity. However, it is inherently susceptible to mutant cells that fail to differentiate. These mutants outcompete normal cells by excessive self-renewal. It remains unclear what mechanisms can resist such mutant expansion. Here, we demonstrate a solution by engineering a synthetic differentiation circuit in Escherichia coli that selects against these mutants via a biphasic fitness strategy. The circuit provides tunable production of synthetic analogs of stem, progenitor, and differentiated cells. It resists mutations by coupling differentiation to the production of an essential enzyme, thereby disadvantaging non-differentiating mutants. The circuit selected for and maintained a positive differentiation rate in long-term evolution. Surprisingly, this rate remained constant across vast changes in growth conditions. We found that transit-amplifying cells (fast-growing progenitors) underlie this environmental robustness. Our results provide insight into the stability of differentiation and demonstrate a powerful method for engineering evolutionarily stable multicellular consortia.
DOI: 10.1016/j.cell.2024.01.024
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00061-8
来源：科学网 小柯机器人