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首页> 外文会议>Cell culture engineering conference >METABOLIC REGULATION OF FUNCTIONAL DECLINE DURING IN VITRO EXPANSION OF HUMAN MESENCHYMAL STEM CELLS
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METABOLIC REGULATION OF FUNCTIONAL DECLINE DURING IN VITRO EXPANSION OF HUMAN MESENCHYMAL STEM CELLS

机译：人间充质干细胞体外扩增过程中功能下降的代谢调控

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Human mesenchymal stem cells (hMSCs) isolated from various adult tissues are primary candidates in cell therapy and being tested in clinical trials for a wide range of diseases. The pro-regenerative and therapeutic properties of hMSCs are largely attributed to their trophic effects that coordinately modulate the progression of inflammation and enhance the endogenous tissue repair by host progenitor cells. However, immediately after isolation and upon culture expansion, hMSCs lose their in vivo quiescent state and start to accumulate genetic and phenotypic changes that significantly alter their phenotypic properties with reduced clonogenic population and therapeutic potential [1]. The culture-induced changes lead to both cellular senescence and metabolic alteration, resulting in reduced therapeutic outcome in various disease models. Since clinical application requires defined cellular properties and large-scale production of hMSCs, preserving cellular homeostasis during hMSCs in vitro expansion is a major barrier for hMSCs-based therapy and production. Once viewed as a mere consequence of the state of a cell, metabolism is now known to play active roles in regulating cellular events that govern stem cell phenotype and age-related functional properties during in vitro culture. Replicative passaging of hMSCs leads to cellular senescence following with insufficient energy production, decline of sternness and functional properties. Here, we report that energy metabolism in regulating hMSC aging-related properties due to in vitro replicative culture expansion in 2D planner or spinner flask bioreactor. hMSCs under in vitro culture up to 15 passages exhibited higher senescence with significant morphological alteration. ~(13)C-glucose-based GC-MS metabolomics analysis suggested that metabolically heterogeneity at low passage hMSCs population while metabolic shift from glycolysis towards OXPHOS at high passage hMSCs. Rapid production of energy required for maintaining cellular properties of hMSCs alters mitochondrial function and leads to breakdown of cellular homeostasis with metabolic and redox imbalance. The alteration of metabolic profile and disruption of cellular homeostasis results in the replicative senescence and decline of therapeutic potentials of hMSCs. Understanding of hMSCs aging during in vitro culture expansion provides the insight of metabolic regulation for stem cell fate and engineering aspects for preserving and rejuvenating hMSCs functions via 3D culture or restore of metabolic balance [2].
机译：从各种成人组织中分离出来的人间充质干细胞（hMSCs）是细胞疗法的主要候选药物，并已在临床试验中针对多种疾病进行测试。 hMSC的再生和治疗特性在很大程度上归因于其营养作用，它们协调调节炎症的进程并增强宿主祖细胞对内源性组织的修复作用。然而，在分离后和培养扩增后，hMSC立即失去其体内静止状态，并开始积累遗传和表型变化，从而显着改变其表型特性，同时降低了克隆形成种群和治疗潜力[1]。培养物引起的变化导致细胞衰老和代谢改变，从而导致各种疾病模型的治疗结果降低。由于临床应用需要确定的hMSCs的细胞特性和大规模生产，因此在hMSCs体外扩增过程中保持细胞稳态是基于hMSCs的治疗和生产的主要障碍。曾经被视为仅是细胞状态的结果，现在已知新陈代谢在调节细胞事件方面起着积极作用，这些事件在干细胞培养过程中控制着干细胞表型和与年龄相关的功能特性。 hMSCs的复制传代导致细胞衰老，伴随着能量产生不足，严厉性和功能特性下降。在这里，我们报告能量代谢在调节hMSC衰老相关的属性，由于在2D规划器或旋转瓶生物反应器中的体外复制培养扩展。在体外培养的多达15代的hMSCs表现出较高的衰老和明显的形态学改变。 〜（13）C-葡萄糖为基础的GC-MS代谢组学分析表明，低传代hMSCs群体的代谢异质性，而高传代hMSCs的代谢则从糖酵解转向OXPHOS。维持hMSCs细胞特性所需的能量快速产生会改变线粒体功能，并导致细胞稳态与代谢和氧化还原不平衡的破坏。代谢特征的改变和细胞稳态的破坏导致hMSCs的复制衰老和治疗潜能的下降。对体外培养扩增过程中hMSCs老化的了解，为干细胞命运的代谢调控提供了见识，并为通过3D培养或恢复代谢平衡来恢复和恢复hMSCs功能的工程方面提供了见解[2]。

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