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. 2020 Feb;34(2):232-240.
doi: 10.1038/s41433-019-0684-8. Epub 2019 Nov 25.

The myofibroblast, biological activities and roles in eye repair and fibrosis. A focus on healing mechanisms in avascular cornea

Maxime Rocher  1 , Pierre-Yves Robert  1 , Alexis Desmoulière  2
Affiliations

The myofibroblast, biological activities and roles in eye repair and fibrosis. A focus on healing mechanisms in avascular cornea

Maxime Rocher et al. Eye (Lond). 2020 Feb.

Abstract
in English, Chinese

Tissue healing is one of the mysteries of modern medicine. Healing involves complex processes and many cellular types, amongst which the myofibroblast plays a major role. In the eye, when needed, myofibroblasts can be found from the cornea to the retina, derived from a wide variety of different cells, and aimed at effectively repairing tissue damage. Myofibroblast differentiation requires transforming growth factor (TGF)-β1, the presence of specific extracellular matrix components such as the ED-A domain of fibronectin, and mechanical tension. Control of this process may, in some cases, be abnormal leading to development of fibrotic tissue, which alters and compromises the integrity of the original tissue. The eye is no exception to this rule with normal visual function, a highly demanding process, only possible in a fully integrated organ. The cornea, a transparent protective tissue and first dioptre of the eye, has the particularity of being entirely avascular and very richly innervated under normal physiological conditions. However, these anatomical features do not prevent it from developing myofibroblasts in the event of a deep corneal lesion. Activated by growth factors such as TGF-β1 and platelet-derived growth factor from the aqueous humour, tears or corneal epithelial cells, myofibroblasts can cause corneal scarring, sometimes with devastating consequences. Understanding the factors involved in healing and its signalling pathways, will potentially enable us to control corneal healing in the future, and thus avoid fibrotic ocular surface disease and the blindness that this may induce. Currently, this issue is the subject of very active research and development with the aim of discovering new antifibrotic therapies.

摘要: 组织修复/愈合是现代医学的奥秘之一。修复/愈合涉及复杂的过程和多种细胞类型, 其中肌成纤维细胞起主要作用。必要时, 在眼内从角膜到视网膜都能发现源自不同种类细胞的肌成纤维细胞, 作用在于有效地修复组织损伤。肌成纤维细胞的分化需要转化生长因子 (TGF) -β1和特定的细胞外基质成分, 如纤维连接蛋白的ED-A结构域和机械张力。在某些情况下, 对这个过程的干预可能是不正常的, 导致纤维组织异常增殖, 这将会改变和破坏原始组织的完整性。眼睛也不例外, 正常的视觉功能, 是一个要求极高的过程, 只有在一个结构完整的器官才能执行。角膜是一层透明的保护组织, 也是眼的第一层屈光组织, 在正常生理条件下具有完全无血管和受丰富神经支配的特性。然而这些解剖特点并不能阻止它在深部角膜损伤转变为肌成纤维细胞。肌成纤维细胞被生长因子如TGF-β1和来自房水、泪液或角膜上皮细胞的血小板衍生生长因子—可导致角膜瘢痕形成, 有时会带来毁灭性的后果。了解角膜愈合的相关因素及其信号通路传导途径, 将有助于我们在未来控制角膜的愈合过程, 从而避免纤维性眼表疾病和其可能的致盲。这个问题是当前研究中的热门课题, 其目的是发现新的抗纤维疗法。.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Illustration showing the appearance of the myofibroblast phenotype during normal repair conditions. Fully differentiated myofibroblasts possess stress fibres expressing α-smooth muscle actin (dotted lines) and secrete important amount of extracellular matrix (ECM). Pro-fibrotic cytokines such as transforming growth factor-β1, ECM components such as ED-A fibronectin and the mechanical microenvironment are all involved in myofibroblastic differentiation. Myofibroblasts are highly contractile cells that stiffen the ECM, leading to an activation of pro-fibrotic growth factors, further stimulating the activation of new myofibroblasts
Fig. 2
Fig. 2
Schematic diagram of the corneal wound healing process. a Implementation of the healing process. Corneal injury involves rupture of the corneal epithelial layer and of the Bowman’s membrane. The anterior stroma therefore is highly exposed to cytokines and others growth factors, particularly transforming growth factor-β1 (TGFß1) and platelet-derived growth factor (PDGF), from corneal epithelial cells, aqueous humour, conjunctiva and tears. Under the influence of active TGFß1, keratocytes of the anterior stroma and/or cells derived from bone marrow, which normally are in a quiescent state, transdifferentiate into myofibroblasts, proliferate and then spread to the site of the lesion by centripetal migration. b Physiological wound healing. Epithelial cells migrate and epithelial proliferation appears. Myofibroblasts synthesize new extracellular matrix (ECM). In the absence of pathological phenomena, myofibroblasts disappear by interleukin (IL)-1-induced apoptosis and tissue transparency is maintained. c Pathological conditions. Myofibroblasts live on and continue to secrete excessive amounts of aberrant ECM proteins. This situation leads to fibrosis and the clinical onset of corneal opacification. This chronic corneal injury subsequently induces corneal neoangiogenesis
Fig. 3
Fig. 3
Corneal neovascularization in pathological situations. Recurrent stromal herpetic keratitis on corneal graft, 8 years after penetrating keratoplasty. This leads to corneal opacities responsible for a major loss of vision for the patient and a very probable risk of graft rejection
Fig. 4
Fig. 4
Sub-basal nervous plexus in a healthy patient, shown using confocal microscopy. The fibres are derived from the sub-epithelial nerve plexus after crossing the Bowman layer. This combined image shows the complex architecture and interconnections of nerve fibres within the sub-basal area, constituting, in the form of a vortex, one of the densest nervous networks in the organism
See this image and copyright information in PMC

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