Mesenchymal stem cells regulate airway contractile tissue remodeling in murine experimental asthma

Abstract

BackgroundMesenchymal stem cells may offer therapeutic potential for asthma due to their immunomodulatory properties and host tolerability, yet prior evidence suggests that bloodborne progenitor cells may participate in airway remodeling. Here, we tested whether mesenchymal stem cells administered as anti‐inflammatory therapy may favor airway remodeling and therefore be detrimental.MethodsAdipose tissue‐derived mesenchymal stem cells were retrovirally transduced to express green fluorescent protein and intravenously injected into mice with established experimental asthma induced by repeat intranasal house dust mite extract. Controls were house dust mite‐instilled animals receiving intravenous vehicle or phosphate‐buffered saline‐instilled animals receiving mesenchymal stem cells. Data on lung function, airway inflammation, and remodeling were collected at 72 h after injection or after 2 weeks of additional intranasal challenge.ResultsThe mesenchymal stem cells homed to the lungs and rapidly downregulated airway inflammation in association with raised T‐helper‐1 lung cytokines, but such effect declined under sustained allergen challenge despite a persistent presence of mesenchymal stem cells. Conversely, airway hyperresponsiveness and contractile tissue underwent a late reduction regardless of continuous pathogenic stimuli and inflammatory rebound. Tracking of green fluorescent protein did not show mesenchymal stem cell integration or differentiation in airway wall tissues.ConclusionsTherapeutic mesenchymal stem cell infusion in murine experimental asthma is free of unwanted pro‐remodeling effects and ameliorates airway hyper‐responsiveness and contractile tissue remodeling. These outcomes support furthering the development of mesenchymal stem cell‐based asthma therapies, although caution and solid preclinical data building are warranted.

Stem cells in animal asthma models: a systematic review

“…In one experiment, MSCs were administered at the beginning of a second challenge at days 76e78, a first challenge having occurred at days 14e16. However, a significant reduction in the BAL total cell count was seen in other studies with repeated challenge such as the Mariñas-Pardo [12] study, in which challenge occurred 3 times weekly for 4 or 6 weeks, and the Ogulur [14] study, in which challenge occurred twice weekly for 12 weeks. The mean cell count ratio in the MSC group compared with the control group is illustrated in Figure 2.…”

“…The most common allergen used was ovalbumin (15 studies), with other studies that used ragweed [9], toluene diisocyanate [10], house-dust mite [11,12], aspergillus fungal extract [13] and cockroach extract [11]. The studies varied in duration, up to 118 days [14].…”

“…One other study used adipose tissue MSCs [19] and another used compact bone MSCs [14]. MSC administration occurred before allergen challenge most commonly but also occurred before sensitization [11,17,20,21] or after allergen challenge [12,14,15,18,22] in other studies. MSCs were administered intravenously in all but 3 studies [11,23,24] in which they were administered intratracheally.…”

“…One exception was the Lathrop et al [13] Th17 inflammation study. The other exception was the experiment in the Mariñas-Pardo [12] study, in which the outcome was assessed 72 h after MSC administration, after 4 weeks of housedust mite instillation. When BAL fluid was obtained 2 weeks after MSC administration, a significant reduction in BAL eosinophils was seen [12].…”

“…The other exception was the experiment in the Mariñas-Pardo [12] study, in which the outcome was assessed 72 h after MSC administration, after 4 weeks of housedust mite instillation. When BAL fluid was obtained 2 weeks after MSC administration, a significant reduction in BAL eosinophils was seen [12]. Again, studies with the most precise estimates include some with a treatment effect closer to unity but also some with the largest effect sizes.…”