Mohammadalipour Amina, Dumbali Sandeep P, Wenzel Pamela L
Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States.
Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States.
Front Cell Dev Biol. 2020 Dec 7;8:603292. doi: 10.3389/fcell.2020.603292. eCollection 2020.
Mesenchymal stromal cell (MSC) metabolism plays a crucial role in the surrounding microenvironment in both normal physiology and pathological conditions. While MSCs predominantly utilize glycolysis in their native hypoxic niche within the bone marrow, new evidence reveals the importance of upregulation in mitochondrial activity in MSC function and differentiation. Mitochondria and mitochondrial regulators such as sirtuins play key roles in MSC homeostasis and differentiation into mature lineages of the bone and hematopoietic niche, including osteoblasts and adipocytes. The metabolic state of MSCs represents a fine balance between the intrinsic needs of the cellular state and constraints imposed by extrinsic conditions. In the context of injury and inflammation, MSCs respond to reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), such as damaged mitochondria and mitochondrial products, by donation of their mitochondria to injured cells. Through intercellular mitochondria trafficking, modulation of ROS, and modification of nutrient utilization, endogenous MSCs and MSC therapies are believed to exert protective effects by regulation of cellular metabolism in injured tissues. Similarly, these same mechanisms can be hijacked in malignancy whereby transfer of mitochondria and/or mitochondrial DNA (mtDNA) to cancer cells increases mitochondrial content and enhances oxidative phosphorylation (OXPHOS) to favor proliferation and invasion. The role of MSCs in tumor initiation, growth, and resistance to treatment is debated, but their ability to modify cancer cell metabolism and the metabolic environment suggests that MSCs are centrally poised to alter malignancy. In this review, we describe emerging evidence for adaptations in MSC bioenergetics that orchestrate developmental fate decisions and contribute to cancer progression. We discuss evidence and potential strategies for therapeutic targeting of MSC mitochondria in regenerative medicine and tissue repair. Lastly, we highlight recent progress in understanding the contribution of MSCs to metabolic reprogramming of malignancies and how these alterations can promote immunosuppression and chemoresistance. Better understanding the role of metabolic reprogramming by MSCs in tissue repair and cancer progression promises to broaden treatment options in regenerative medicine and clinical oncology.
间充质基质细胞（MSC）代谢在正常生理和病理状态下的周围微环境中起着至关重要的作用。虽然MSC在骨髓中其天然的低氧微环境中主要利用糖酵解，但新证据揭示了线粒体活性上调在MSC功能和分化中的重要性。线粒体和线粒体调节因子（如沉默调节蛋白）在MSC稳态以及向骨骼和造血微环境的成熟谱系（包括成骨细胞和脂肪细胞）分化中发挥关键作用。MSC的代谢状态代表了细胞状态的内在需求与外在条件施加的限制之间的精细平衡。在损伤和炎症的背景下，MSC通过将其线粒体捐赠给受损细胞来响应活性氧（ROS）和损伤相关分子模式（DAMP），如受损的线粒体和线粒体产物。通过细胞间线粒体运输、ROS调节和营养利用的改变，内源性MSC和MSC疗法被认为通过调节受损组织中的细胞代谢发挥保护作用。同样，这些相同的机制在恶性肿瘤中也可能被利用，即线粒体和/或线粒体DNA（mtDNA）转移到癌细胞会增加线粒体含量并增强氧化磷酸化（OXPHOS），从而有利于增殖和侵袭。MSC在肿瘤起始、生长和治疗抵抗中的作用存在争议，但其改变癌细胞代谢和代谢环境的能力表明MSC在改变恶性肿瘤方面处于核心地位。在本综述中，我们描述了MSC生物能量学适应的新证据，这些适应协调了发育命运决定并促进了癌症进展。我们讨论了在再生医学和组织修复中针对MSC线粒体进行治疗靶向的证据和潜在策略。最后，我们强调了在理解MSC对恶性肿瘤代谢重编程的贡献以及这些改变如何促进免疫抑制和化疗耐药性方面的最新进展。更好地理解MSC代谢重编程在组织修复和癌症进展中的作用有望拓宽再生医学和临床肿瘤学的治疗选择。
