Functional Effects of TGF-β1 on Mesenchymal Stem Cell Mobilization in Cockroach Allergen–Induced Asthma

Abstract

Mesenchymal stem cells (MSCs) have been suggested to participate in immune regulation and airway repair/remodeling. Transforming growth factor β1 (TGFβ1) is critical in the recruitment of stem/progenitor cells for tissue repair, remodeling and cell differentiation. In this study, we sought to investigate the role of TGFβ1 in MSC migration in allergic asthma. We examined nestin expression (a marker for MSCs) and TGFβ1 signaling activation in airways in cockroach allergen (CRE) induced mouse models. Compared with control mice, there were increased nestin+ cells in airways, and higher levels of active TGFβ1 in serum and p-Smad2/3 expression in lungs of CRE-treated mice. Increased activation of TGFβ1 signaling was also found in CRE-treated MSCs. We then assessed MSC migration induced by conditioned medium (ECM) from CRE-challenged human epithelium in air/liquid interface (ALI) culture in Transwell assays. MSC migration was stimulated by ECM, but was significantly inhibited by either TGFβ1 neutralizing antibody or TβR1 inhibitor. Intriguingly, increased migration of MSCs from blood and bone marrow to the airway was also observed after systemic injection of GFP+-MSCs, and from bone marrow of Nes-GFP mice following CRE challenge. Furthermore, TGFβ1 neutralizing antibody inhibited the CRE-induced MSC recruitment, but promoted airway inflammation. Finally, we investigated the role of MSCs in modulating CRE induced T cell response, and found that MSCs significantly inhibited CRE-induced inflammatory cytokine secretion (IL-4, IL13, IL17 and IFN-γ) by CD4+ T cells. These results suggest that TGFβ1 may be a key pro-migratory factor in recruiting MSCs to the airways in mouse models of asthma.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…The authors suggested that MSCs recruited to the site of injury would exert their antiinflammatory properties and alleviate pathogenesis. It is worth noting that this study failed to show whether circulating Nes-GFP MSCs were present in peripheral blood, nor did the authors eliminate the possibility that tissue resident MSCs simply proliferated, thereby contributing to MSC accumulation (Gao et al, 2014). On the contrary, Chen and colleagues detected circulating MSCs in the peripheral blood of mice that had undergone acute liver injury.…”

“…Whether bone marrow (BM) MSCs circulate in humans has been the subject of debate (Hoogduijn et al, 2014;Mansilla et al, 2006;Wang et al, 2006). Despite this, recent studies conducted in animal models of injury have provided robust evidence that endogenous bone marrow-derived stromal cells can circulate and localise in injured tissue (Chen et al, 2010;Gao et al, 2014;Hong et al, 2009;Shu et al, 2013). In a study by Gao et al, endogenous Nestin+ MSCs were recruited to the lungs of Nes-GFP-transgenic mice challenged intranasally with cockroach allergen.…”

“…In a study by Gao et al, endogenous Nestin+ MSCs were recruited to the lungs of Nes-GFP-transgenic mice challenged intranasally with cockroach allergen. Histological studies showed activated transforming growth factor (TGF)-β1 signalling in challenged airways, and TGF-β1 was found to enhance the chemotactic activity of MSCs using in vitro chemotaxis assays (Gao et al, 2014). The authors suggested that MSCs recruited to the site of injury would exert their antiinflammatory properties and alleviate pathogenesis.…”

Aberrant TGF-β activation in bone tendon insertion induces enthesopathy-like disease

“…Active TGF-β induces mesenchymal stromal stem cell (MSC) migration to the bone-resorptive pits for new bone formation (31). However, excessive active TGF-β leads to uncoupled bone remodeling, contributing to the pathogenesis of rare genetic skeletal diseases such as Camurati-Engelmann disease (CED), osteogenesis imperfecta, and more common musculoskeletal disorders, such as osteoarthritis (31)(32)(33)(34)(35)(36). High levels of TGF-β have been observed locally lower in relation to sham-operated controls ( Figure 1B).…”

“…Our previous study showed that high concentrations of active TGF-β1 in subchondral bone increased the number of MSCs and osteoprogenitors to disrupt the joint microarchitecture and contributed to the pathogenesis of osteoarthritis (36). Injection of TGF-β-neutralizing antibody has been shown to improve several skeletal diseases in animal models, such as CED, osteoarthritis, and osteogenesis imperfecta (31)(32)(33)(34)(35). Excessive release of active TGF-β has also been found to contribute to tendon and cartilage pathology, leading to massive tenocyte death (60) and cartilage degeneration (61).…”