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      MSC Based Therapies—New Perspectives for the Injured Lung

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          Abstract

          Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.

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          Most cited references134

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          Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease.

          Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants. Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD. Neonatal mice exposed to hyperoxia (75% O(2)) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile. Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC-CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation. BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.
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            Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.

            Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.
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              Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage.

              Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                03 March 2020
                March 2020
                : 9
                : 3
                : 682
                Affiliations
                [1 ]Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; Judith.Behnke@ 123456paediat.med.uni-giessen.de (J.B.); Sarah.Kremer@ 123456paediat.med.uni-giessen.de (S.K.); Tayyab.Shahzad@ 123456paediat.med.uni-giessen.de (T.S.); Cho-Ming.Chao@ 123456paediat.med.uni-giessen.de (C.-M.C.)
                [2 ]Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), German Center for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany; Saverio.Bellusci@ 123456innere.med.uni-giessen.de
                [3 ]Institute of Virology, Philipps University Marburg, Hans-Meerwein-Strasse 2, 35043 Marburg, Germany; friebertshaeuser@ 123456staff.uni-marburg.de
                [4 ]Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Ludwigstrasse 43, 61231 Bad Nauheim, Germany; rory.morty@ 123456mpi-bn.mpg.de
                Author notes
                [* ]Correspondence: Harald.Ehrhardt@ 123456paediat.med.uni-giessen.de ; Tel.: +49-985-43400; Fax: +49-985-43419
                Author information
                https://orcid.org/0000-0003-4307-8759
                https://orcid.org/0000-0001-5987-4579
                https://orcid.org/0000-0003-4587-1734
                Article
                jcm-09-00682
                10.3390/jcm9030682
                7141210
                32138309
                b334d985-7801-4dfc-a014-df62e0f36825
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 11 February 2020
                : 28 February 2020
                Categories
                Review

                mesenchymal stem cells,msc,chronic lung disease,lung repair,extracellular vesicles,bronchopulmonary dysplasia,asthma,chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis,inflammation,lung injury

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