The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication
Section snippets
Merely an introduction
Fibrosis is commonly described as degeneration of connective tissue where excessive accumulation of fibrillar, collagen-rich extracellular matrix (ECM) replaces functional tissue. However, deposition and organization of fibrotic scar tissue is essential to restore and maintain organ integrity after injury or chronic overload. Tissue repair is fast because it mainly uses ECM to fix the damage as opposed to true tissue or organ regeneration that restores the appropriate cell and ECM components [1,
Mutual mechanisms mediate healing and fibrosis
Normal repair occurs in a highly regulated sequence of overlapping phases comprising hemostasis, inflammation, proliferation, and remodeling/maturation [3,4]. The ECM performs central functions at all stages, both as a reinforcing material and cell instructor [[5], [6], [7], [8]]. Wound healing often starts with activated platelets forming a provisional ECM with cross-linked fibrin, fibronectin, fibrinogen, and proteoglycans. The provisional ECM mechanically stabilizes the damage and
Macrophage modes
Macrophages can be recruited from tissue-resident sources or bone marrow-derived circulating monocytes [[34], [35], [36], [37]]. Macrophages from both progenies seem to play distinct roles in repair, with evidence from heart [38], lung [39,40], and skin [[40], [41], [42]]. For mechanistic cell culture studies (and reasons of simplicity), macrophages are often ‘classically activated’ into M1 by treatment with interferon-γ and lipopolysaccharides, and ‘alternatively activated’ into M2 by
Myofibroblasts make massive matrix and matrix mechanics modulate myofibroblasts
ECM production (‘fibroblast’) and contraction (‘myo’) are the primary roles of myofibroblasts, likely performed in subsequent stages of their activation program [20]. In addition to fibrillar collagen types I and III [24], other proteins are enriched in the myofibroblast ECM and partly used as diagnostic markers of fibrosis, such as ED-A fibronectin [123], tenascin-C [124], type VI collagen, and matricellular proteins periostin [95,[125], [126], [127]] and CCN2 [128]. The reader is referred to
Moral
The molecular composition and physical properties of ECM can dictate the fate and function of resident cells and mediate intercellular communication by transmitting mechanical signals. In conditions of tissue repair and fibrosis the ECM plays a critical role in spatially and temporally coordinating complex cellular and molecular events, not unlike developmental processes. In contrast to acute communication through paracrine signals or direct intercellular contact formation, ECM cues can persist
Funding
The research of BH is supported by the Canadian Institutes of Health Research (CIHR), Foundation Grant # 375597.
Conflict
The authors have declared that no conflict of interest exists.
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