Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia.
Laboratory of Molecular Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
Int J Mol Sci. 2023 Oct 16;24(20):15212. doi: 10.3390/ijms242015212.
Liver diseases, characterized by high morbidity and mortality, represent a substantial medical problem globally. The current therapeutic approaches are mainly aimed at reducing symptoms and slowing down the progression of the diseases. Organ transplantation remains the only effective treatment method in cases of severe liver pathology. In this regard, the development of new effective approaches aimed at stimulating liver regeneration, both by activation of the organ's own resources or by different therapeutic agents that trigger regeneration, does not cease to be relevant. To date, many systematic reviews and meta-analyses have been published confirming the effectiveness of mesenchymal stromal cell (MSC) transplantation in the treatment of liver diseases of various severities and etiologies. However, despite the successful use of MSCs in clinical practice and the promising therapeutic results in animal models of liver diseases, the mechanisms of their protective and regenerative action remain poorly understood. Specifically, data about the molecular agents produced by these cells and mediating their therapeutic action are fragmentary and often contradictory. Since MSCs or MSC-like cells are found in all tissues and organs, it is likely that many key intercellular interactions within the tissue niches are dependent on MSCs. In this context, it is essential to understand the mechanisms underlying communication between MSCs and differentiated parenchymal cells of each particular tissue. This is important both from the perspective of basic science and for the development of therapeutic approaches involving the modulation of the activity of resident MSCs. With regard to the liver, the research is concentrated on the intercommunication between MSCs and hepatocytes under normal conditions and during the development of the pathological process. The goals of this review were to identify the key factors mediating the crosstalk between MSCs and hepatocytes and determine the possible mechanisms of interaction of the two cell types under normal and stressful conditions. The analysis of the hepatocyte-MSC interaction showed that MSCs carry out chaperone-like functions, including the synthesis of the supportive extracellular matrix proteins; prevention of apoptosis, pyroptosis, and ferroptosis; support of regeneration; elimination of lipotoxicity and ER stress; promotion of antioxidant effects; and donation of mitochondria. The underlying mechanisms suggest very close interdependence, including even direct cytoplasm and organelle exchange.
肝脏疾病具有高发病率和死亡率的特点，是全球范围内一个重大的医学问题。目前的治疗方法主要旨在减轻症状和减缓疾病的进展。在严重的肝脏病理情况下，器官移植仍然是唯一有效的治疗方法。在这方面，开发新的有效方法来刺激肝脏再生，无论是通过激活器官自身的资源，还是通过触发再生的不同治疗剂，都不失为一种相关的方法。迄今为止，已经发表了许多系统评价和荟萃分析，证实了间充质基质细胞（MSC）移植在治疗各种严重程度和病因的肝脏疾病方面的有效性。然而，尽管 MSC 在临床实践中的成功应用和动物肝脏疾病模型中具有有前途的治疗结果，但它们的保护和再生作用的机制仍知之甚少。具体而言，关于这些细胞产生的分子剂及其介导治疗作用的数据是零碎的，并且经常相互矛盾。由于 MSC 或 MSC 样细胞存在于所有组织和器官中，因此组织龛内的许多关键细胞间相互作用可能都依赖于 MSC。在这种情况下，了解 MSC 与特定组织的分化实质细胞之间的通讯机制至关重要。这从基础科学的角度和涉及调节驻留 MSC 活性的治疗方法的发展两方面来看都是很重要的。就肝脏而言，研究集中在正常情况下和病理过程发展过程中 MSC 与肝细胞之间的相互通信。本综述的目的是确定介导 MSC 和肝细胞之间串扰的关键因素，并确定两种细胞类型在正常和应激条件下相互作用的可能机制。对肝细胞-MSC 相互作用的分析表明，MSC 发挥伴侣样功能，包括支持细胞外基质蛋白的合成；防止细胞凋亡、细胞焦亡和铁死亡；支持再生；消除脂毒性和内质网应激；促进抗氧化作用；以及捐赠线粒体。潜在的机制表明它们之间存在非常密切的相互依存关系，甚至包括直接的细胞质和细胞器交换。
