The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation

Abstract

Various forms of fibrosis, comprising tissue thickening and scarring, are involved in 40% of deaths across the world. Since the discovery of scarless functional healing in fetuses prior to a certain stage of development, scientists have attempted to replicate scarless wound healing in adults with little success. While the extracellular matrix (ECM), fibroblasts, and inflammatory mediators have been historically investigated as separate branches of biology, it has become increasingly necessary to consider them as parts of a complex and tightly regulated system that becomes dysregulated in fibrosis. With this new paradigm, revisiting fetal scarless wound healing provides a unique opportunity to better understand how this highly regulated system operates mechanistically. In the following review, we navigate the four stages of wound healing (hemostasis, inflammation, repair, and remodeling) against the backdrop of adult versus fetal wound healing, while also exploring the relationships between the ECM, effector cells, and signaling molecules. We conclude by singling out recent findings that offer promising leads to alter the dynamics between the ECM, fibroblasts, and inflammation to promote scarless healing. One factor that promises to be significant is fibroblast heterogeneity and how certain fibroblast subpopulations might be predisposed to scarless healing. Altogether, reconsidering fetal wound healing by examining the interplay of the various factors contributing to fibrosis provides new research directions that will hopefully help us better understand and address fibroproliferative diseases, such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.

Time-lapsed proteomics reveals a role for the novel protein, SNED1, in modulating ECM composition and protein folding

“…Our view of the ECM has significantly changed over the past decades, from an inert scaffold to a remarkably complex and dynamic signaling platform. We now know that the ECM is actively remodeled over time during the processes of development, tissue aging, wound healing, and disease progression [4,7,8,10,12]. Changes in cell-ECM interactions, microenvironmental cues (e.g., tissue oxygenation levels), and environmental factors (e.g., smoke, UV) induce .…”

“…The ECM also conveys biochemical and biomechanical signals that tightly control all cellular processes from cell proliferation and survival, to migration, to differentiation [1,5]. Alterations of ECM structure and/or composition arising from mutations in ECM genes, or from an imbalance in ECM homeostasis, e.g., excessive accumulation or degradation, lead to, or accompany, many pathological processes including skeletal diseases, cardiovascular diseases, fibrosis, and cancer [6][7][8][9][10][11][12]. To understand the underlying molecular bases of ECM involvement in diseases, we need methods and tools capable of probing the complexity of this compartment.…”

A Comprehensive Review of Natural Compounds for Wound Healing: Targeting Bioactivity Perspective

“…For fibroblasts to migrate in the extracellular matrix, they must first recognize and interact with particular matrix components. Fibroblasts in the normal dermis are usually dormant and sparsely scattered, but they are active and plentiful in the provisional matrix wound site and granulation tissue [ 24 , 25 ]. Their migration and aggregation in the wound site necessitate morphological changes and the production and secretion of proteases to clear a passage from the ECM into the wound site.…”

Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System

“…Fundamentally, the inflammatory response is one that is designed to enhance survival after an injury (i.e., a cut in the skin) or exposure to environmental threats, such as microorganisms. After an injury to a tissue, the inflammatory response can also facilitate repair via clearance of damaged tissue components or microorganisms, and then initiate the fibrotic process with formation of a scar tissue, a process that is central to wound healing success as reviewed in [ 23 ]. Thus, scar formation in response to the injury of some tissues offers a survival advantage, but for MSK tissues that function in defined mechanical environments, scar tissue is not adequate for the optimal functioning of tissues, such as tendons, ligaments and menisci.…”

“…The timing of the onset of the ability to mount an inflammatory response during development has provided some interesting insights into the relationship(s) between tissue development and inflammation. Thus, the organization template of tissues and organs appears prior to an ability to mount an effective inflammatory response; however, some aspects of this relationship are still controversial as discussed in [ 23 , 33 , 34 ]. Injuries in some locations, such as cutaneous wounds, heal by regeneration if incurred early in fetal life, but they heal with the formation of scar tissue after the onset of effective inflammatory response capabilities are in place.…”