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Effect of nutrient metabolism on cartilaginous tissue formation
Biotechnology and Bioengineering ( IF 3.8 ) Pub Date : 2021-07-15 , DOI: 10.1002/bit.27888
Roberto Tarantino 1, 2 , Loraine L Y Chiu 2 , Joanna F Weber 2 , Man Yat Tse 3 , Davide D Bardana 4 , Stephen C Pang 3 , Stephen D Waldman 1, 2
Affiliation  

A major shortcoming in cartilage tissue engineering is the low biosynthetic response of chondrocytes. While different strategies have been investigated, a novel approach may be to control nutrient metabolism. Although known for their anaerobic metabolism, chondrocytes are more synthetically active under conditions that elicit mixed aerobic–anaerobic metabolism. Here, we postulate this metabolic switch induces HIF-1α signaling resulting in improved growth. Transition to different metabolic states can result in the pooling of metabolites, several of which can stabilize HIF-1α by interfering with PHD2. Chondrocytes cultured under increased media availability accelerated tissue deposition with the greatest effect occurring at 2 ml/106 cells. Under higher media availability, metabolism switched from anaerobic to mixed aerobic-anaerobic. Around this transition, maximal changes in PHD2 activity, HIF-1α expression, and HIF-1 target gene expression were observed. Loss-of-function studies using YC-1 confirmed the involvement of HIF-1. Lastly, targeted metabolomic studies revealed that intracellular lactate and succinate correlated with PHD2 activity. This study demonstrates that cartilaginous tissue formation can be regulated by nutrient metabolism and that this response is mediated through changes in HIF-1α signaling. By harnessing this newly identified metabolic switch, engineered cartilage implants may be developed without the need for sophisticated methods which could aid translation to the clinic.

中文翻译:

营养代谢对软骨组织形成的影响

软骨组织工程的一个主要缺点是软骨细胞的低生物合成反应。虽然已经研究了不同的策略,但一种新的方法可能是控制营养代谢。尽管以无氧代谢而闻名,但软骨细胞在引发混合有氧-无氧代谢的条件下更具合成活性。在这里,我们假设这种代谢开关诱导 HIF-1α 信号传导,从而改善生长。过渡到不同的代谢状态会导致代谢物的汇集,其中一些可以通过干扰 PHD2 来稳定 HIF-1α。在增加的培养基可用性下培养的软骨细胞加速了组织沉积,在 2 ml/10 6时效果最大细胞。在较高的培养基可用性下,代谢从厌氧转变为混合好氧-厌氧。围绕这一转变,观察到 PHD2 活性、HIF-1α 表达和 HIF-1 靶基因表达的最大变化。使用 YC-1 的功能丧失研究证实了 HIF-1 的参与。最后,靶向代谢组学研究表明,细胞内乳酸和琥珀酸与 PHD2 活性相关。这项研究表明,软骨组织的形成可以通过营养代谢来调节,并且这种反应是通过 HIF-1α 信号传导的变化来介导的。通过利用这种新发现的代谢开关,可以开发工程软骨植入物,而无需复杂的方法来帮助转化为临床。
更新日期:2021-09-12
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