Mesenchymal stem cells and serelaxin synergistically abrogate established airway fibrosis in an experimental model of chronic allergic airways disease

Abstract

This study determined if the anti-fibrotic drug, serelaxin (RLN), could augment human bone marrow-derived mesenchymal stem cell (MSC)-mediated reversal of airway remodeling and airway hyperresponsiveness (AHR) associated with chronic allergic airways disease (AAD/asthma). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD were either untreated or treated with MSCs alone, RLN alone or both combined from weeks 9-11. Changes in airway inflammation (AI), epithelial thickness, goblet cell metaplasia, transforming growth factor (TGF)-β1 expression, myofibroblast differentiation, subepithelial and total lung collagen deposition, matrix metalloproteinase (MMP) expression, and AHR were then assessed. MSCs alone modestly reversed OVA-induced subepithelial and total collagen deposition, and increased MMP-9 levels above that induced by OVA alone (all p<0.05 vs OVA group). RLN alone more broadly reversed OVA-induced epithelial thickening, TGF-β1 expression, myofibroblast differentiation, airway fibrosis and AHR (all p<0.05 vs OVA group). Combination treatment further reversed OVA-induced AI and airway/lung fibrosis compared to either treatment alone (all p<0.05 vs either treatment alone), and further increased MMP-9 levels. RLN appeared to enhance the therapeutic effects of MSCs in a chronic disease setting; most likely a consequence of the ability of RLN to limit TGF-β1-induced matrix synthesis complemented by the MMP-promoting effects of MSCs.

Intranasal administration of mesenchymoangioblast‐derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease

“…Twenty‐four hours after the establishment of chronic AAD (on d 64), subgroups of Ova‐ or Sal‐sensitized/challenged mice ( n = 8 mice/group) underwent IV or IN administration of MCA‐MSCs. In all cases, a 14‐d treatment period (from d 64 to 77) was chosen to replicate the time frame used to evaluate the intranasally delivered effects of other stem cells, such as human bone marrow–derived (stromal) MSCs (15, 28) and human amnion epithelial cells (28), in the Ova‐induced chronic model of AAD.…”

“…For IV administration of MCA‐MSCs, 1 × 10 7 cells were resuspended in 2 ml PBS. Mice were restrained in a Perspex restrainer (Perspex Distribution, Chelmsford, United Kingdom), and 1 × 10 6 cells/200 μl PBS were injected into the tail vein of Sal‐ or Ova‐sensitized/challenged mice, which is a commonly used cell concentration delivered to mice (13, 15, 20, 28). For IN administration of MCA‐MSCs, 1 × 10 7 cells were resuspended in 0.5 ml of PBS.…”

“…MSCs also home to the injured tissue through the expression of the chemokine receptor type 4, and the expression of this receptor is heightened in a proinflammatory environment such as in asthma, enhancing their homing ability (14). MSCs can also be administered directly into the lungs via intranasal (IN) instillation (15) and via the intratracheal route (12, 16).…”

“…Because iPSCs can proliferate indefinitely and because MCAs can expand into extremely large quantities of MSCs, sufficient MCA‐MSCs can be acquired from a single master cell bank of iPSCs derived from a single healthy blood donor (limiting donor‐ and expansion‐dependent variability and contamination from nontarget cells) without the need for excessive culture expansion once MSCs are formed. In this study, we investigated the therapeutic potential of these MCA‐MSCs when delivered to a well‐established murine model of chronic AAD, which presents with the 3 central features of human asthma: AI, AWR, and AHR (15, 27). In particular, we compared the antiremodeling effects of IV vs.…”

Novel Anti-fibrotic Therapies

“…Recent studies also showed efficacy of intranasal relaxin administration in allergic airway disease and cigarette smoke induced lung damage (Royce et al, 2014; Pini et al, 2016). In an exciting development, relaxin and bone marrow-derived mesenchymal stem cells or amnionic epithelial stem cells were found to be synergistic in the treatment of established airway disease (Royce et al, 2015, 2016). The mechanism for this effect is currently under investigation, but appears to be related to the matrix remodeling and anti-TGFβ effects of relaxin promoting a favorable environment for the establishment of stem cell residency in the damaged tissue (Samuel et al, 2016b).…”