Therapeutic administration of bone marrow-derived mesenchymal stromal cells reduces airway inflammation without upregulating Tregs in experimental asthma

Abstract

Background

Prophylactic administration of mesenchymal stromal cells (MSCs) derived from adipose (AD-MSC) and bone marrow tissue (BM-MSC) in ovalbumin-induced asthma hinders inflammation in a Treg-dependent manner. It is uncertain whether MSCs act through Tregs when inflammation is already established in asthma induced by a clinically relevant allergen.

Objective

Evaluate the effect of therapeutic administration of MSCs on inflammation and Treg cells in house dust mite (HDM)-induced asthma.

Methods

BM-MSCs and AD-MSCs were administered intratracheally to C57BL/6 mice 1 day after the last HDM challenge. Lung function, remodeling and parenchymal inflammation, were assayed 3 or 7 days after MSCs treatment, through invasive plethysmography and histology, respectively. Bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes (mLNs) were assessed for lymphocyte phenotyping by flow cytometry. MSCs were studied regarding their potential to induce Treg cells from primed and unprimed lymphocytes in vitro.

Results

BM-MSCs, but not AD-MSCs, reduced lung influx of eosinophils and B cells and increased IL-10 levels in HDM-challenged mice. Neither BM-MSCs nor AD-MSCs reduced lung parenchymal inflammation, airway hyperresponsiveness or mucus hypersecretion. BM- and AD-MSCs did not upregulate Treg cell counts within the airways and mLNs, but BM-MSCs decreased the pro-inflammatory profile of alveolar macrophages. Co-culture of BM-MSCs and AD-MSCs with allergen-stimulated lymphocytes reduced Treg cell counts in a cell to cell contact independent manner, although co-culture of both MSCs with unprimed lymphocytes upregulated Treg cell counts.

Conclusions

MSCs therapeutically administered exert anti-inflammatory effects in the airway of HDM-challenged mice, but do not ameliorate lung function or remodeling. Although MSC pre-treatment can increase Treg cell numbers, it is highly unlikely that the MSCs will induce Treg cell expansion when lymphocytes are allergenically primed in an established lung inflammation.

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