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

Abstract

Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (Ova)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to 11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. Ova-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-β1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all < 0.001 uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA-MSCs to Ova-injured mice. In comparison, intranasal delivery of MCA-MSCs to Ova-injured mice significantly decreased all parameters measured (all < 0.05 Ova group) and, most notably, normalized aberrant airway TGF-β1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

iPSC‐ and mesenchymoangioblast‐derived mesenchymal stem cells provide greater protection against experimental chronic allergic airways disease compared with a clinically used corticosteroid

“…Even epithelial repair factors that do not have any effects on chronic AAD‐induced total lung collagen concentration levels were found to modestly suppress AHR (19). Above all, we have found that therapies that target aberrant collagen levels are most effective in reducing chronic AAD‐induced AHR over other ECM proteins or AWR parameters (14, 19, 22, 23).…”

“…Separate serial sections were immunohistochemically stained for TGF‐β1 using a pAb (sc‐146, 1:1000 dilution; Santa Cruz Biotechnology, Dallas, TX, USA); α‐smooth muscle actin (a marker of myofibroblast differentiation) using an mAb (M0851, 1:200 dilution; Agilent Technologies, Santa Clara, CA, USA); or thymic stromal lymphopoietin (TSLP) (a marker for epithelial damage) using a pAb (ABT330, 1:1000 dilution; MilliporeSigma). Morphometric analysis of all end points was performed in a blinded fashion as previously described (14, 19, 22, 23).…”

The mesenchymoangioblast, mesodermal precursor for mesenchymal and endothelial cells

“…MB-based mesenchymal cell generation protocols, in contrast to protocols based on spontaneous hPSC differentiation, allow for standardized manufacturing of well-defined pure MSC, PC and SMC cell populations for clinical applications. The therapeutic efficacy of MB-derived MSCs has been demonstrated in animal models of hindlimb ischemia and chronic allergic airways disease [101,102]. Further animal and in vitro studies are needed to compare the therapeutic potential of MB-derived MSCs and various PC subsets, to explore whether more specific and efficient targeting of inflammation versus tissue degeneration could be achieved with these populations.…”

“…In hindlimb ischemia, intramuscular injection of MB-derived MSCs inhibited tissue damage, improved peripheral blood flow and significantly reduced toe necrosis, suggesting that these cells have a significant protective effect against ischemic insult [101]. Royce et al [102], induced chronic allergic airways disease (AAD)/asthma by administering aerosolized ovalbumin to ovalbumin-sensitized mice. After establishing chronic AAD, mice were treated with MSCs administered intravenously or intranasally.…”

Intranasal delivery of human umbilical cord Wharton's jelly mesenchymal stromal cells restores lung alveolarization and vascularization in experimental bronchopulmonary dysplasia

“…37,38 Conversely, a study in mice with ovalbumin-induced asthma similarly demonstrated abrogation of airway injury after intranasal administration of MSCs. 39 Additionally, these investigators demonstrated that intranasal delivery was more successful in reducing lung fibrosis, inflammation, and airway reactivity than the intravenous route.…”