Agudelo Luis Ramirez, Yarmush Gabriel, Kumar Suneel, Berthiaume Francois
Department of Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Biology (Basel). 2025 Jun 18;14(6):722. doi: 10.3390/biology14060722.
Accelerating healing is a clinical goal in both acute and chronic non-healing skin wounds. We leveraged the public Recon database, which seeks to aggregate all of the metabolic pathways in the human body, to uncover whether increasing the supply of specific metabolites can bolster cellular metabolism and, in turn, enhance wound healing. The database was reduced to a set of 357 reactions and 339 metabolites that were better suited for human cells in culture. Monte Carlo simulations were performed to identify the impact of 25 different inputs on the metabolic fluxes within the cellular biochemical network. Biomass and ATP production were used as surrogate markers for cell proliferation and cell migration (an energy-intensive process), respectively, both of which are critical to wound healing. The subset of simulations yielding the highest ATP production or biomass production were those where glycine and/or glutamine uptake was increased. Maximizing ATP and biomass also generally increased oxygen uptake. Due to its low availability in chronic wounds, another set of simulations was carried out in which oxygen uptake was held constant to mimic the effect of a limited oxygen supply. However, even with this constraint, glycine and glutamine remained the most promising interventions. The predictions were tested in vitro using immortalized human keratinocytes. Amino acid uptake was tentatively increased by supplementing the base culture media with additional glycine and/or glutamine, with valine supplementation with a similar nitrogen load as a control. Glycine supplementation significantly increased cellular proliferation above the base media and accelerated wound closure rate in wound scratch assay. However, glutamine and valine supplementation did not improve these parameters above base media, and glutamine even suppressed the benefit of glycine in cultures supplemented with both amino acids. In conclusion, glycine supplementation enhances cellular processes that are associated with wound healing.
加速愈合是急性和慢性难愈合皮肤伤口的一个临床目标。我们利用了公共的Recon数据库（该数据库旨在汇总人体所有的代谢途径）来探究增加特定代谢物的供应是否能促进细胞代谢，进而增强伤口愈合。该数据库被精简为一组更适合培养中的人类细胞的357个反应和339种代谢物。进行了蒙特卡洛模拟，以确定25种不同输入对细胞生化网络内代谢通量的影响。生物量和ATP生成分别用作细胞增殖和细胞迁移（一个能量密集型过程）的替代标志物，这两者对伤口愈合都至关重要。产生最高ATP生成量或生物量生成量的模拟子集是那些甘氨酸和/或谷氨酰胺摄取增加的情况。使ATP和生物量最大化通常也会增加氧气摄取。由于其在慢性伤口中的可用性较低，进行了另一组模拟，其中氧气摄取保持恒定以模拟有限氧气供应的效果。然而，即使有这个限制，甘氨酸和谷氨酰胺仍然是最有前景的干预措施。这些预测在体外使用永生化的人角质形成细胞进行了测试。通过在基础培养基中额外补充甘氨酸和/或谷氨酰胺来暂时增加氨基酸摄取，以补充具有相似氮负荷的缬氨酸作为对照。补充甘氨酸显著提高了基础培养基之上的细胞增殖，并在伤口划痕试验中加速了伤口闭合率。然而，补充谷氨酰胺和缬氨酸并没有在基础培养基之上改善这些参数，并且谷氨酰胺甚至在同时补充两种氨基酸的培养物中抑制了甘氨酸的益处。总之，补充甘氨酸可增强与伤口愈合相关的细胞过程。
