Management of fibrosis: the mesenchymal stromal cells breakthrough

Abstract

Fibrosis is the endpoint of many chronic inflammatory diseases and is defined by an abnormal accumulation of extracellular matrix components. Despite its slow progression, it leads to organ malfunction. Fibrosis can affect almost any tissue. Due to its high frequency, in particular in the heart, lungs, liver, and kidneys, many studies have been conducted to find satisfactory treatments. Despite these efforts, current fibrosis management therapies either are insufficiently effective or induce severe adverse effects. In the light of these facts, innovative experimental therapies are being investigated. Among these, cell therapy is regarded as one of the best candidates. In particular, mesenchymal stromal cells (MSCs) have great potential in the treatment of inflammatory diseases. The value of their immunomodulatory effects and their ability to act on profibrotic factors such as oxidative stress, hypoxia, and the transforming growth factor-β1 pathway has already been highlighted in preclinical and clinical studies. Furthermore, their propensity to act depending on the microenvironment surrounding them enhances their curative properties. In this paper, we review a large range of studies addressing the use of MSCs in the treatment of fibrotic diseases. The results reported here suggest that MSCs have antifibrotic potential for several organs.

Figure 1

Fibrotic pathologies in various organs. Common features of fibrosis development and progression in various organs and related diseases (ECM: extracellular matrix).

Figure 2

Fibrosis is a multicomponent pathology driven by multiple factors. Fibrotic diseases are driven by multiple factors such as inflammatory reaction, hypoxia, and oxidative stress leading to the activation of the TGF-β1 pathway (DC: dendritic cell, EMT: epithelial-to-mesenchymal transition, LAP: latency associated protein, MMP: matrix metalloproteinase, RNS: reactive nitrogen species, ROS: reactive oxygen species, Smad: small mothers against decapentaplegic homolog, TGF: transforming growth factor, and TIMP: tissue inhibitor of metalloproteinases).

Figure 3

MSCs exert various effects on immune cells. A summary of MSC-mediated effects on the immune response. Various factors secreted by MSC exert an inhibitory effect on cells of the immune system which are involved in the fibrotic process (HGF: hepatocyte growth factor, HLA: human leukocyte antigen, IDO: indoleamine 2,3-dioxygenase, IFN-γ: interferon-γ, Ig: immunoglobulin, IL: interleukin, MSC: mesenchymal stromal cell, NO: nitric oxide, PGE2: prostaglandin E2, Tc: cytotoxic T-cell, TGF-β: transforming growth factor-β, TNF-α: tumor necrosis factor-α, Th: helper T-cell, and Treg: regulatory T-cell).

Figure 4

Common outcome of MSC therapy for various fibrotic diseases. Based on the studies reported in this work, several mechanisms have been underlined, mostly concerning inflammatory reaction and apoptosis, oxidative stress/hypoxia modulation, and extracellular matrix remodeling. It appears that MSC secretome activates a wide range of antifibrotic pathways (ECM: extracellular matrix, EMT: epithelial-to-mesenchymal transition, LAP: latency associated protein, MMP: matrix metalloproteinase, MSC: mesenchymal stromal cell, TGF-β: transforming growth factor-β, and TIMP: tissue inhibitor of metalloproteinase).