Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model

Lee²,

et al. 2018

Front. Pharmacol.

The objective of this study was to investigate the effect of human adipose tissue-derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1ß (MIP-1ß), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of Fc𝜀RIβ with histone deacetylase 3 (HDAC3) and Lyn, increased ß-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA-3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR-122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti-atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs.

Section: Discussionmentioning

confidence: 99%

Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses

Lee²,

et al. 2018

Front. Pharmacol.

“…To date, several methods have been developed for the induction of bronchial asthma using different animal models. For example, cotton dust, OVA, Ascaris lumbricoides antigens, cockroach extracts (Blatella germanica), house dust mite extract (HDM) (Dermatophagoides pteronyssinus, Dermatophagoides farina), fungi, and molds (Aspergillus fumigatus, Alternaria alternata), ragweed, latex (Hevea brasiliensis), and bacterial lipopolysaccharide (LPS) are allergens commonly implicated in asthma development and exacerbations [10][11][12][13]. Besides, the application of Alum via intraperitoneal route followed by airway challenges induces an acute allergic response that will mask immune events that are only partially contributing to inflammation and airway hyper-responsiveness [12,14].…”

Section: Introductionmentioning

confidence: 99%

Unraveling the therapeutic effects of mesenchymal stem cells in asthma

et al. 2020

Asthma is a chronic inflammatory disease associated with airway hyper-responsiveness, chronic inflammatory response, and excessive structural remodeling. The current therapeutic strategies in asthmatic patients are based on controlling the activity of type 2 T helper lymphocytes in the pulmonary tissue. However, most of the available therapies are symptomatic and expensive and with diverse side outcomes in which the interruption of these modalities contributes to the relapse of asthmatic symptoms. Up to date, different reports highlighted the advantages and beneficial outcomes regarding the transplantation of different stem cell sources, and relevant products from for the diseases’ alleviation and restoration of injured sites. However, efforts to better understand by which these cells elicit therapeutic effects are already underway. The precise understanding of these mechanisms will help us to translate stem cells into the clinical setting. In this review article, we described current knowledge and future perspectives related to the therapeutic application of stem cell-based therapy in animal models of asthma, with emphasis on the underlying therapeutic mechanisms.

Stem Cells Translational Medicine

“…In previous studies, a single dose of MSCs administered prophylactically or therapeutically reduced lung influx of inflammatory cells, airway hyperresponsiveness, and mucus hypersecretion in models of ovalbumin-induced allergic asthma. 3,7,8,22,23 In HDM-induced allergic asthma, a single dose of MSCs administered prophylactically also prevented inflammation by modulating epithelial cell activation. 24 However, effects on the inflammatory process were only marginal, with no improvements in lung function and remodeling when MSCs were administered therapeutically.…”

Section: Discussionmentioning

confidence: 99%

“…Mesenchymal stromal cell (MSC) therapy has demonstrated promising results in several lung disease models, but its impact on airway remodeling has been sometimes controversial . In models of ovalbumin‐ and Aspergillus hyphal extract‐induced allergic asthma, a single dose of MSCs administered either locally or systemically resulted in reduction of both lung inflammation and remodeling . Conversely, in house dust mite extract (HDM)‐induced allergic asthma, a single dose of MSCs reduced some inflammatory parameters but was unable to ameliorate lung function or remodeling .…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6] In models of ovalbuminand Aspergillus hyphal extract-induced allergic asthma, a single dose of MSCs administered either locally or systemically resulted in reduction of both lung inflammation and remodeling. 3,[7][8][9][10] Conversely, in house dust mite extract (HDM)-induced allergic asthma, a single dose of MSCs reduced some inflammatory parameters but was unable to ameliorate lung function or remodeling. 4,5 Some reports have indicated that repeated cell-based therapy yielded better therapeutic effects, either by preventing disease progression or by further reducing inflammation and remodeling, in experimental silicosis and elastase-induced emphysema.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Castro

Kitoko

Xisto

et al. 2019

In experimental house dust mite (HDM)-induced allergic asthma, therapeutic administration of a single dose of adipose tissue-derived mesenchymal stromal cells (MSCs) ameliorates lung inflammation but is unable to reverse remodeling. We hypothesized that multiple doses of MSCs might exert better therapeutic effects by reducing lung inflammation and remodeling but might also result in immunosuppressive effects in experimental asthma. HDM was administered intranasally in C57BL/6 mice. After the last HDM challenge, mice received two or three doses of MSCs (10 5 cells per day) or salineintravenously. An additional cohort of mice received dexamethasone as a positive control for immunosuppression. Two and three doses of MSCs reduced lung inflammation; levels of interleukin (IL)-4, IL-13, and eotaxin; total leukocyte, CD4 + T-cell, and eosinophil counts in bronchoalveolar lavage fluid; and total leukocyte counts in bone marrow, spleen, and mediastinal lymph nodes. Two and three doses of MSCs also reduced collagen fiber content and transforming growth factor-β levels in lung tissue; however, the three-dose regimen was more effective, and it reduced these parameters to control levels, while also decreasing α-actin content in lung tissue. Two and three doses of MSCs improved lung mechanics. Dexamethasone and two and three doses of MSCs similarly increased galectin levels, but only the three-dose regimen increased CD39 levels in the thymus. Dexamethasone and the three-dose, but not the two-dose, regimen also increased the levels of programmed death receptor-1 and IL-10, while reducing CD4 + CD8 low cell percentage in the thymus. In conclusion, multiple doses of MSCs reduced lung inflammation and remodeling while causing immunosuppression in HDM-induced allergic asthma. K E Y W O R D Sadipose stem cells, cellular therapy, immunosuppression, lung, mesenchymal stromal cells