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Tissue alignment enhances remodeling potential of tendon-derived cells - Lessons from a novel microtissue model of tendon scarring.
Matrix Biology ( IF 4.5 ) Pub Date : 2017-06-22 , DOI: 10.1016/j.matbio.2017.06.002
Jasper Foolen 1 , Stefania L Wunderli 2 , Sandra Loerakker 3 , Jess G Snedeker 2
Affiliation  

Tendinopathy is a widespread and unresolved clinical challenge, in which associated pain and hampered mobility present a major cause for work-related disability. Tendinopathy associates with a change from a healthy tissue with aligned extracellular matrix (ECM) and highly polarized cells that are connected head-to-tail, towards a diseased tissue with a disorganized ECM and randomly distributed cells, scar-like features that are commonly attributed to poor innate regenerative capacity of the tissue. A fundamental clinical dilemma with this scarring process is whether treatment strategies should focus on healing the affected (disorganized) tissue or strengthen the remaining healthy (anisotropic) tissue. The question was thus asked whether the intrinsic remodeling capacity of tendon-derived cells depends on the organization of the 3D extracellular matrix (isotropic vs anisotropic). Progress in this field is hampered by the lack of suitable in vitro tissue platforms. We aimed at filling this critical gap by creating and exploiting a next generation tissue platform that mimics aspects of the tendon scarring process; cellular response to a gradient in tissue organization from isotropic (scarred/non-aligned) to highly anisotropic (unscarred/aligned) was studied, as was a transient change from isotropic towards highly anisotropic. Strikingly, cells residing in an 'unscarred' anisotropic tissue indicated superior remodeling capacity (increased gene expression levels of collagen, matrix metalloproteinases MMPs, tissue inhibitors of MMPs), when compared to their 'scarred' isotropic counterparts. A numerical model then supported the hypothesis that cellular remodeling capacity may correlate to cellular alignment strength. This in turn may have improved cellular communication, and could thus relate to the more pronounced connexin43 gap junctions observed in anisotropic tissues. In conclusion, increased tissue anisotropy was observed to enhance the cellular potential for functional remodeling of the matrix. This may explain the poor regenerative capacity of tenocytes in chronic tendinopathy, where the pathological process has resulted in ECM disorganization. Additionally, it lends support to treatment strategies that focus on strengthening the remaining healthy tissue, rather than regenerating scarred tissue.

中文翻译:

组织对齐可增强肌腱衍生细胞的重塑潜力-新型肌腱瘢痕微组织模型的经验教训。

肌腱病是一项广泛且尚未解决的临床挑战,其中相关的疼痛和行动不便是造成与工作有关的残疾的主要原因。腱鞘病与从具有对齐的细胞外基质(ECM)和头对尾相连的高度极化的细胞的健康组织向具有无组织的ECM和随机分布的细胞的病变组织的变化有关,这种变化通常归因于疤痕样特征导致组织固有的再生能力差。这种疤痕形成过程的基本临床难题是治疗策略应集中在治愈受累(杂乱无章)的组织还是加强其余健康(各向异性)的组织。因此提出了一个问题,即肌腱来源的细胞的固有重塑能力是否取决于3D细胞外基质的组织(各向同性与各向异性)。缺乏合适的体外组织平台阻碍了该领域的进展。我们旨在通过创建和利用模仿腱瘢痕形成过程的下一代组织平台来填补这一关键空白。研究了细胞对组织结构从各向同性(疤痕/不对齐)到高度各向异性(无疤痕/对齐)的梯度的反应,以及从各向同性向高度各向异性的短暂变化。令人惊讶的是,存在于“无疤”各向异性组织中的细胞显示出卓越的重塑能力(胶原蛋白,基质金属蛋白酶MMPs,MMPs组织抑制剂的基因表达水平提高),与“疤痕”各向同性的同类相比。然后,数值模型支持了细胞重塑能力可能与细胞排列强度相关的假设。这反过来可能会改善细胞通讯,因此可能与在各向异性组织中观察到的更明显的connexin43间隙连接有关。总之,观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为重点在于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。然后,数值模型支持了细胞重塑能力可能与细胞排列强度相关的假设。这反过来可能会改善细胞通讯,因此可能与在各向异性组织中观察到的更明显的connexin43间隙连接有关。总之,观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为专注于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。然后,数值模型支持了细胞重塑能力可能与细胞排列强度相关的假设。这反过来可能会改善细胞通讯,因此可能与在各向异性组织中观察到的更明显的connexin43间隙连接有关。总之,观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为专注于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。这反过来可能会改善细胞通讯,因此可能与在各向异性组织中观察到的更明显的connexin43间隙连接有关。总之,观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为专注于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。这反过来可能会改善细胞通讯,因此可能与在各向异性组织中观察到的更明显的connexin43间隙连接有关。总之,观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为专注于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为重点在于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。观察到增加的组织各向异性增强了基质功能重构的细胞潜力。这可以解释慢性肌腱病中肌腱细胞再生能力差,其中病理过程导致ECM紊乱。此外,它为专注于增强剩余健康组织而不是再生疤痕组织的治疗策略提供了支持。
更新日期:2019-11-01
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