Computational Models Provide Insight into In Vivo Studies and Reveal the Complex Role of Fibrosis in mdx Muscle Regeneration.
Computational Models Provide Insight into In Vivo Studies and Reveal the Complex Role of Fibrosis in mdx Muscle Regeneration.
复制标题
计算模型提供了对体内研究的深入了解，并揭示了纤维化在 mdx 肌肉再生中的复杂作用。
DOI：
10.1007/s10439-020-02566-1
复制
发表时间：
2021
影响因子：
3.8
通讯作者：
Blemker,SilviaS
中科院分区：
文献类型：
--
作者：
Virgilio,KelleyM;Jones,BrianK;Miller,EmilyY;Ghajar-Rahimi,Elnaz;Martin,KyleS;Peirce,ShaynM;Blemker,SilviaS
杜氏肌营养不良症是一种促纤维化、肌肉消耗性疾病。减少纤维化是一个潜在的治疗目标;然而，其对肌肉再生的影响尚未完全了解。本研究（1）使用基于代理的模型来预测mdx肌肉中纤维化增加对损伤再生的影响，以及（2）实验测试所产生的模型衍生的假设。该模型预测，由于生长因子扩散受限和细胞迁移受损，增加纤维化面积分数会降低损伤后28天的再生。WT、mdx和TGFβ处理的mdx小鼠被用于实验测试。TGFβ注射增加了细胞外基质（ECM）面积分数;然而，被认为与ECM蛋白密度相关的经处理肌肉的被动刚度在注射后降低，表明ECM蛋白密度较低。此外，在恢复期间，两组之间没有横截面积（CSA）差异。额外的模拟显示，降低ECM蛋白密度导致CSA没有差异，与实验相似。这些结果表明，单独增加ECM面积分数不足以降低mdx肌肉的再生能力，并且纤维化是一种复杂的病理状况，需要进一步了解。
Duchenne muscular dystrophy is a pro-fibrotic, muscle wasting disease. Reducing fibrosis is a potential therapeutic target; however, its effect on muscle regeneration is not fully understood. This study (1) used an agent-based model to predict the effect of increased fibrosis inmdxmuscle on regeneration from injury, and (2) experimentally tested the resulting model-derived hypothesis. The model predicted that increasing the area fraction of fibrosis decreased regeneration 28 days post injury due to limited growth factor diffusion and impaired cell migration. WT,mdx, and TGFβ-treatedmdxmice were used to test this experimentally. TGFβinjections increased the extracellular matrix (ECM) area fraction; however, the passive stiffness of the treated muscle, which was assumed to correlate with ECM protein density, decreased following injections, suggesting that ECM protein density was lower. Further, there was no cross-sectional area (CSA) difference during recovery between the groups. Additional simulations revealed that decreasing the ECM protein density resulted in no difference in CSA, similar to the experiment. These results suggest that increases in ECM area fraction alone are not sufficient to reduce the regenerative capacity of mdx muscle, and that fibrosis is a complex pathological condition requiring further understanding.