Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts

Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary‐like structures. The release of microvesicles from Hmyos was dose‐dependently induced by the serum protein α‐2‐macroglobulin. Using flow cytometry, we revealed the presence of the α‐2‐macroglobulin receptor—low‐density lipoprotein receptor‐related protein 1—on the surface of Hmyos. The inhibition of the binding of α‐2‐macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α‐2‐Macroglobulin modulates the release of these microvesicles through interaction with low‐density lipoprotein receptor‐related protein 1.     

The pig as a model system for investigating the recruitment and contribution of myofibroblasts in skin healing

In the skin-healing field, porcine models are regarded as a useful analogue for human skin due to their numerous anatomical and physiological similarities. Despite the widespread use of porcine models in skin healing studies, the initial origin, recruitment and transition of fibroblasts to matrix-secreting contractile myofibroblasts are not well defined for this model. In this review, we discuss the merit of the pig as an animal for studying myofibroblast origin, as well as the challenges associated with assessing their contributions to skin healing. Although a variety of wound types (incisional, partial thickness, full thickness, burns) have been investigated in pigs in attempts to mimic diverse injuries in humans, direct comparison of human healing profiles with regards to myofibroblasts shows evident differences. Following injury in porcine models, which often employ juvenile animals, myofibroblasts are described in the developing granulation tissue at 4 days, peaking at Days 7–14, and persisting at 60 days post-wounding, although variations are evident depending on the specific pig breed. In human wounds, the presence of myofibroblasts is variable and does not correlate with the age of the wound or clinical contraction. Our comparison of porcine myofibroblast-mediated healing processes with those in humans suggests that further validation of the pig model is essential. Moreover, we identify several limitations evident in experimental design that need to be better controlled, and standardisation of methodologies would be beneficial for the comparison and interpretation of results. In particular, we discuss anatomical location of the wounds, their size and depth, as well as the healing microenvironment (wet vs. moist vs. dry) in pigs and how this could influence myofibroblast recruitment. In summary, although a widespread model used in the skin healing field, further research is required to validate pigs as a useful analogue for human healing with regards to myofibroblasts.     

槟榔碱诱导人脐静脉内皮细胞表达α-SMA的实验研究

目的：检测氯沙坦干预下、槟榔碱诱导的人脐静脉内皮细胞（HUVECs）表达α-SMA的情况。方法：用不同浓度槟榔碱刺激HUVECs,采用免疫细胞印迹法检测各组HUVECs中α-SMA的表达。再以固定槟榔碱浓度诱导HUVECs,不同浓度氯沙坦干预,检测各组HUVECs中α-SMA的表达。结果：槟榔碱可诱导HUVECs表达α-SMA,经氯沙坦干预后α-SMA的表达受到一定抑制。结论：HUVECs经槟榔碱刺激后可转化为表达α-SMA的肌成纤维细胞。血管紧张素Ⅱ受体拮抗剂氯沙坦可部分抑制这种转化,提示血管紧张素Ⅱ及其受体参与了槟榔碱诱导的内皮-间充质转化。     

Expression analysis of α-smooth muscle actin and tenascin-C in the periodontal ligament under orthodontic loading or in vitro culture

α-smooth muscle actin (α-SMA) and tenascin-C are stress-induced phenotypic features of myofibroblasts. The expression levels of these two proteins closely correlate with the extracellular mechanical microenvironment. We investigated how the expression of α-SMA and tenascin-C was altered in the periodontal ligament (PDL) under orthodontic loading to indirectly reveal the intrinsic mechanical microenvironment in the PDL. In this study, we demonstrated the synergistic effects of transforming growth factor-β1 (TGF-β1) and mechanical tensile or compressive stress on myofibroblast differentiation from human periodontal ligament cells (hPDLCs). The hPDLCs under higher tensile or compressive stress significantly increased their levels of α-SMA and tenascin-C compared with those under lower tensile or compressive stress. A similar trend was observed in the tension and compression areas of the PDL under continuous light or heavy orthodontic load in rats. During the time-course analysis of expression, we observed that an increase in α-SMA levels was matched by an increase in tenascin-C levels in the PDL under orthodontic load in vivo. The time-dependent variation of α-SMA and tenascin-C expression in the PDL may indicate the time-dependent variation of intrinsic stress under constant extrinsic loading.     

Emerging targets for the treatment of scleroderma

Introduction: Scleroderma is an often-fatal autoimmune connective tissue disease. Recommendations for treating digital ulcers and pulmonary hypertension in scleroderma have recently been established by the European League Against Rheumatism. Conversely, although many valuable insights have been generated into the molecular mechanism underlying the persistent fibrotic phenotype in scleroderma, no safe, clinically proven effective treatment has been found for this aspect of the disease.

Areas covered: Recent evidence suggests that, based on genome-wide molecular profiling, scleroderma can be loosely divided into ‘fibroproliferative' and ‘inflammatory' cohorts. The latter cohort contains patients with localized and ‘limited' disease, as well as a small subset of those with ‘diffuse' disease. Drugs targeting either B cells or ILs might be useful to treat patients who possess an ‘inflammatory' gene expression signature.

Expert opinion: In the future, a ‘personalized medicine' approach might be used to treat patients with scleroderma: individuals with an ‘inflammatory' gene expression signature may be successfully treated with drugs specifically targeting the immune system. Indeed, drugs currently approved for other rheumatic disease might also be used to treat scleroderma patients bearing an ‘inflammatory' gene expression profile.     

The fate of myofibroblasts during the development of fibrosis in Crohn's disease

Intestinal fibrosis is a devastating complication in patients with inflammatory bowel disease. Its characteristics include the loss of regular peristalsis and nutrition absorption, excessive deposition of extracellular matrix (ECM) components, thickness of intestinal lumen due to the formation of strictures and of scar tissue. As a major cell type involved in fibrogenesis, the myofibroblasts have already been shown to have a plastic and heterogeneous function in producing abundant collagen, fibronectin and connective tissue growth factor. The primary sources of ECM‐producing and vimentin‐positive myofibroblasts come from different precursor cells, including bone marrow‐derived mesenchymal cells, fibrocytes, pericytes, epithelial to mesenchymal transition and endothelial to mesenchymal transition. Recent immunological research findings suggest that numerous cytokines and chemokines made from macrophages, in addition to T cells and other myeloid cell types, are also important drivers of myofibroblast differentiation and hence of the activation of myofibroblast‐mediated transforming growth factor and collagen production. In this review we discuss the origins, roles and cell signaling of myofibroblasts during the development of fibrosis in different organs, particularly in Crohn's disease. Finally, we suggest that the epigenetic and immunological regulation of myofibroblast differentiation may provide a novel antifibrotic strategy in the near future.