Cell-Based Therapies for Tissue Fibrosis

Abstract

The development of tissue fibrosis in the context of a wound-healing response to injury is common to many chronic diseases. Unregulated or persistent fibrogenesis may lead to structural and functional changes in organs that increase the risk of significant morbidity and mortality. We will explore the natural history, epidemiology, and pathogenesis of fibrotic disease affecting the lungs, kidneys, and liver as dysfunction of these organs is responsible for a substantial proportion of global mortality. For many patients with end-stage disease, organ transplantation is the only effective therapy to prolong life. However, not all patients are candidates for the major surgical interventions and life-long immunosuppression required for a successful outcome and donor organs may not be available to meet the clinical need. We will provide an overview of the latest treatment strategies for these conditions and will focus on stem or progenitor cell-based therapies for which there is substantial pre-clinical evidence based on animal models as well as early phase clinical trials of cell-based therapy in man.

Therapeutic strategies for enhancing angiogenesis in wound healing

“…Bone marrow derived mesenchymal stem cells (MSCs) are also promising candidates as a cellular therapy for enhancing wound healing (Table 8). MSCs have been found to modulate inflammation at wound sites as well as influence surrounding cells to encourage regeneration as opposed to fibrosis [303][304][305][306]. In one study, researchers used a full-thickness cutaneous wound model in rats to study the wound healing potential of rat MSCs [307].…”

Platelet-Rich Plasma and Bone Marrow-Derived Mesenchymal Stromal Cells Prevent TGF-β1-Induced Myofibroblast Generation but Are Not Synergistic when Combined: Morphological in vitro Analysis

“…The identification of effective therapeutic options aimed to prevent and even more counteract and revert excessive tissue scarring is a current scientific challenge with high clinical priority. This is on the basis of the following considerations: (i) fibrosis frequently occurs in different organs as an aberrant maladaptive reparative re-sponse to extended/severe or chronic injury, often leading to their morpho-functional impairment and endstage organ disease; (ii) therapeutic tools for eradication of the underlying etiology (in some cases resulting in fibrosis resolution) are not always available and, even more, most human fibrotic diseases are often multifactorial in origin, so that a direct action on the noxious causes may be virtually impossible; (iii) current anti-fibrotic therapeutic options adopted so far have a limited efficacy; (iv) fibrosis is estimated to account for up to 50% of all causes of death in industrialized countries [Fang et al, 2017;Lim et al, 2017;Zuccaro et al, 2017;Allinovi et al, 2018;Walraven et al, 2018;Yoon et al, 2019]. In this scenario, therapies aimed to modulate the recognized "core cellular mechanisms of fibrosis" such as generation, functionality, and fate of myofibroblasts, the key effectors of tissue scarring in most organs, could be strategical and promising.…”

“…At the same time, in vitro investigations have identified myofibroblast generation as the target of the potential anti-fibrotic paracrine and juxtacrine action of bone marrow MSCs [Galie and Stegemann, 2014;Sassoli et al, 2014b;Huang et al, 2015;Lan et al, 2015;Jang et al, 2015;Fang et al, 2016]. Eventually, some human trials aimed to evaluate bone marrow MSC-based therapy for those diseases where fibrosis plays a major etiological role and are ongoing [Srour and Thébaud, 2015;Squillaro et al, 2016;Lim et al, 2017;Miao et al, 2017;Rozier et al, 2018]. However, despite this encouraging evidence, some criticisms still exist regarding bone marrow MSC-based therapy, limiting their use in clinical applications including, among others: (i) the need of protocols for ex vivo cell amplification according to GMP guidelines, avoiding the contamination or immunologi-cal reactions towards xenogeneic compounds, such as animal sera, and (ii) the identification of appropriate growth factors and/or bioengineered three-dimensional scaffolds acting both as a pre-conditioning agent and cell delivery vehicle during transplantation, thus enabling to preserve or promote the survival rate, optimize functionality, and improve the engraftment of the injected cells in the host tissue microenvironment.…”

Gli3 is a novel downstream target of miR‑200a with an anti‑fibrotic role for progression of liver fibrosis in�vivo and in�vitro

“…However, many patients with liver fibrosis either do not respond to these treatments or are diagnosed at intermediate or advanced disease stages, where satisfactory curative approaches are often not feasible (4). Additionally, although liver transplantation is a highly successful treatment for end stage liver fibrosis, it is not always possible, due to limited organ availability and the presence of contraindicating comorbidities (5). Therefore, there is an urgent need to develop, test and monitor antifibrotic treatments that can prevent, halt, or even reverse liver fibrosis.…”