Department of Orthopaedics, University Hospital Balgrist, Lengghalde 5, CH-8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Lengghalde 5, CH-8008 Zurich, Switzerland; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Department of Orthopaedics, University Hospital Balgrist, Lengghalde 5, CH-8008 Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Lengghalde 5, CH-8008 Zurich, Switzerland.
Matrix Biol. 2018 Jan;65:14-29. doi: 10.1016/j.matbio.2017.06.002. Epub 2017 Jun 19.
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.
腱病是一种广泛存在且未得到解决的临床挑战，其相关疼痛和运动受限是导致与工作相关残疾的主要原因。腱病与健康组织中细胞排列整齐的细胞外基质（ECM）和高度极化的细胞发生变化有关，这些细胞头尾相连，而病变组织的 ECM 排列紊乱，细胞分布随机，具有类似疤痕的特征，通常归因于组织先天再生能力差。这种疤痕形成过程中的一个基本临床难题是，治疗策略是否应该集中在治愈受影响的（组织排列紊乱）组织，还是增强剩余的健康（各向异性）组织。因此，人们提出了这样一个问题，即肌腱源性细胞的内在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）。由于缺乏合适的体外组织平台，该领域的进展受到阻碍。我们旨在通过创建和利用一种下一代组织平台来填补这一关键空白，该平台模拟了腱病疤痕形成过程的各个方面；研究了细胞对组织组织从各向同性（疤痕/无排列）到高度各向异性（无疤痕/排列）的梯度的反应，以及从各向同性到高度各向异性的短暂变化。令人惊讶的是，与它们的“疤痕”各向同性对应物相比，“无疤痕”各向异性组织中存在的细胞表现出更高的重塑能力（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增加）。然后，数值模型支持了这样一种假设，即细胞重塑能力可能与细胞排列强度相关。这反过来又可能改善了细胞间的通讯，因此可能与在各向异性组织中观察到的更明显的连接蛋白 43 缝隙连接有关。总之，观察到组织各向异性增加可增强基质功能重塑的细胞潜力。这可以解释慢性腱病中腱细胞再生能力差的原因，在慢性腱病中，病理过程导致 ECM 排列紊乱。此外，它支持了关注增强剩余健康组织而不是再生疤痕组织的治疗策略。
