Regulation of myofibroblast activities: Calcium pulls some strings behind the scene

Abstract

Myofibroblast-induced remodeling of collagenous extracellular matrix is a key component of our body's strategy to rapidly and efficiently repair damaged tissues; thus myofibroblast activity is considered crucial in assuring the mechanical integrity of vital organs and tissues after injury. Typical examples of beneficial myofibroblast activities are scarring after myocardial infarct and repair of damaged connective tissues including dermis, tendon, bone, and cartilage. However, deregulation of myofibroblast contraction causes the tissue deformities that characterize hypertrophic scars as well as organ fibrosis that ultimately leads to heart, lung, liver and kidney failure. The phenotypic features of the myofibroblast, within a spectrum going from the fibroblast to the smooth muscle cell, raise the question as to whether it regulates contraction in a fibroblast- or muscle-like fashion. In this review, we attempt to elucidate this point with a particular focus on the role of calcium signaling. We suggest that calcium plays a central role in myofibroblast biological activity not only in regulating contraction but also in mediating intracellular and extracellular mechanical signals, structurally organizing the contractile actin–myosin cytoskeleton, and establishing lines of intercellular communication.

Introduction

The myofibroblast is a specialized cell for connective tissue remodeling. Myofibroblasts are critical for normal wound healing but deregulation of their remodeling functions is associated with fibrosis and pathological contracture. A priori, myofibroblasts contribute to the physiological repair of injured connective tissues such as skin, tendon, bone and cartilage. They ensure tissue integrity by forming a mechanically resistant scar, such as what occurs after a myocardial infarction [1]. Myofibroblasts form scars through two activities: enhanced production of a collagen-rich extracellular matrix (ECM) and organization of this matrix into a mechanically supportive structure, which is accomplished by the application of high contractile forces [1], [2].

Towards the end of physiological wound healing, myofibroblasts normally disappear by apoptosis [3]. When myofibroblasts persist, the same activities that are beneficial for wound healing can lead to tissue deformities and loss of organ function [4]. This phenomenon relates to several important conditions that affect human health such as the hypertrophic scarring of skin seen in burn healing [5], systemic sclerosis [6], [7], and Dupuytren's disease [8]. In organ fibrosis, myofibroblast-generated contractures lead to reduced organ function and failure of the liver [9], [10], [11], heart [12], lung [13], [14], [15], and kidney [16], [17]. In novel therapeutic approaches that are currently being applied in regenerative medicine, there is a risk of tissue-delivered mesenchymal stem cells differentiating into myofibroblasts, which could lead to loss of regenerative potential and deterioration of fibrotic conditions [18], [19]. Myofibroblasts that are activated by engrafted biomaterials [20] such as at breast implant sites, produce tissue contractures around the implant surface similar to those seen in hypertrophic scars, frequently leading to implant malfunction and ultimately failure. Further, myofibroblasts play a crucial role in stromal reactions to epithelial tumors by providing a chemical and mechanical environment that promotes tumor progression [21], [22]. Clearly, identifying the molecules that regulate myofibroblast function would be beneficial for therapeutic control of wound healing, particularly if detrimental side-effects could be avoided. Previously we have reviewed the chemical and mechanical factors that govern the formation of myofibroblasts from different types of precursor cells [23], [24], [25]. Here, we focus on the mechanisms that regulate their contractile activity, a critical function that contributes to tissue remodeling and pathological tissue contracture.