introduction
The intestinal tract is a key organ in direct contact with the external environment, and it is always resistant to the invasion of harmful substances and pathogens. Thanks to its intrinsic stem cell system, the gut has an extraordinary ability to repair itself. However, there is still a lack of comprehensive understanding of how intestinal stem cells (ISCs) sense damage signals and rapidly activate them from a resting state to repair damaged intestinal epithelial tissue through proliferation and differentiation. The research of Chen Haiyang's team at West China Hospital of Sichuan University found that the number of peroxisomes in intestinal stem cells increases significantly when the intestine is damaged, and promotes stem cell differentiation by regulating the JAK-STAT-SOX21 signaling pathway, which plays a regulatory role in the intestinal repair process [1]. However, how peroxisomes in ISCs respond to intestinal epithelial injury signals, and how their numbers change dynamically during injury repair, need to be further elucidated.
2024年7月23日，四川大学华西医院陈海洋团队再次在Developmental Cell杂志上发表了题为Very long-chain fatty acids control peroxisome dynamics via a feedback loop in intestinal stem cells during gut regeneration 的研究。 该研究揭示了肠道损伤后，肠道内的极长链脂肪酸（Very long-chain fatty acids，VLCFAs）含量上升，并作为关键信号分子，通过激活过氧化物酶体增殖体激活受体（peroxisome proliferator-activated receptors，PPARs）与SOX21转录因子之间的负反馈机制，精确调控ISC内过氧化物酶体的动态平衡。 这一发现为理解ISC在肠道损伤后的修复机制提供了新的视角。
In order to explore the dynamic change mechanism of peroxisomes in intestinal stem cells during intestinal injury repair, Chen's team used mouse and fruit fly models to observe that the number of peroxisomes increased significantly in the early stage of intestinal injury and gradually returned to baseline levels in the later stage of repair. The researchers found that the dynamics of very long-chain fatty acids (VLCFAs, fatty acids with a carbon chain length of at least 20 carbon atoms) in free fatty acids were consistent with the trend of peroxisomes (see Figure 1).
图1.损伤早期（DSS-7D）和修复早期（DSS-RE-5D）肠道中VLCFAs增多(Credit: Developmental Cell)
Although the role of VLCFAs in cell membrane structure and lipid metabolism has been extensively studied, their specific physiological functions in animals have rarely been reported. This study revealed for the first time that VLCFAs can act as signaling molecules to activate the activity of intracellular regulatory transcription factors, and precisely control the dynamic changes of peroxisome number in intestinal stem cells during damage repair through a negative feedback mechanism. The researchers found that VLCFAs caused peroxisomes to achieve a delicate balance between division and autophagic degradation by regulating the expression of PPARs and SOX21, two transcriptional regulators, in stem cells after intestinal damage, and transmitted signals downward to affect the endometrial system circulation within the ISC, thereby regulating the differentiation of the ISC to produce new intestinal epithelial cells and returning the ISC to a resting state after repair was completed (Figure 2).
图2.模式图(Credit: Developmental Cell)
In conclusion, this study delved into the detailed mechanism that regulates the dynamic changes in peroxisome number in stem cells after intestinal injury, revealing the key role of VLCFAs as signaling molecules in this process. Studies have confirmed that VLCFAs can promote repair after intestinal injury by regulating the proliferation of peroxisomes. This not only enriches our understanding of stem cell-mediated intestinal repair mechanisms, but also is expected to provide new therapeutic ideas for the clinical treatment of inflammatory bowel disease (IBDs) and other related diseases.
bibliography
1 Du, G. et al. Peroxisome Elevation Induces Stem Cell Differentiation and Intestinal Epithelial Repair. Dev Cell 53,169-184 e111, doi:10.1016/j.devcel.2020.03.002 (2020).https://doi.org/10.1016/j.devcel.2024.06.020
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