Abstract

The regenerative and immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them attractive in the treatment of many diseases. Although they have shown promising preclinical studies of immunomodulation and paracrine effects in inflammatory airway disorders and other lung diseases, there are still challenges that have to be overcome before MSCs can be safely, effectively, and routinely applied in the clinical setting. A good understanding of the roles and mechanisms of the MSC immunomodulatory effects will benefit the application of MSC-based clinical therapy. In this review, we summarize the promises and challenges of the preclinical and clinical trials of MSC therapies, aiming to better understand the role that MSCs play in attempt to treat inflammatory airway disorders.

Introduction

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types, including bone, fat cells, muscle, cartilage, and connective tissue. MSCs can readily be obtained from adult tissues such as umbilical cord, bone marrow, and fat tissue [1,2]. In addition, MSCs derived from pluripotent stem cells like induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) closely resemble conventional bone marrow or adipose‐tissue derived MSC in terms of both phenotype and function [3–5]. This alternative means of MSC generation could, in theory, provide an indefinite supply of MSCs with well‐defined phenotype and functions. MSCs are self-renewable, easily accessible, and culturally expandable with exceptional genomic stability and only a few ethical issues, which make the cells good candidates for cell therapy, regenerative medicine, and tissue repair [2]. MSCs have been proven to possess anti-inflammatory capacity by secreting various cytokines/chemokines, which suppress T-cell-mediated immune responses [6–8]. Due to their regeneration and anti-inflammatory capacities, MSCs are attractive therapeutic cells for many diseases, such as bone and immune diseases. Here, we review the role of MSCs in the treatment of inflammatory airway disorders, mostly focused on promises and challenges of the preclinical and clinical trials of MSC therapies, aiming to better understand the role that MSCs play in the inflammatory airway disorders.

Status of MSC therapies in airway inflammation

The immunomodulatory properties of MSCs make them a promising candidate for the treatment of inflammatory airway disorders. A growing number of preclinical studies on immunomodulation and paracrine effects of MSCs are being performed to provide evidence of safety and efficacy in animal models of asthma, allergic rhinitis (AR), bronchopulmonary dysplasia (BPD), chronic obstructive pulmonary disease (COPD), and other lung diseases [9]. More and more clinical trials are ongoing to examine the MSC therapy in airway inflammation. However, MSC therapies for airway inflammation are still in its infacy.

Allergic airway inflammation

Allergic airway inflammation including asthma and AR is an abnormally exacerbated reaction toward common environmental factors, such as pollen grains, dust mites, or animal dander. The airway inflammation is characterized by wheezing, reversible airway obstruction, airway hyper-responsiveness (AHR), infiltration of eosinophils and type 2 T cells into the airway submucosa, mucus hypersecretion, and airway remodeling [10,11]. Since the discovery of T-helper (Th)1 and Th2 cells in the cluster of differentiation (CD)4+ T-cell subpopulations, it became evident rather quickly that Th2 cells play the crucial role in the development of allergic inflammatory disorders by releasing their specific cytokines interleukin (IL)-4, IL-5, and IL-13. Evidence suggest that a Th type 1/2 imbalance with a Th2-dominant response to inhaled allergens plays a critical role in the pathogenesis of allergic airway inflammation and identified the Th2 cytokines as key effector molecules in this process [12–14]. This concept is well accepted today and has led to the emergence of novel therapeutic approaches interfering with mechanisms of Th2 activation that have entered clinics or showed promising results in clinical studies [15,16]. However, a variety of cell types, including airway epithelial cells, Th2 cells, eosinophils, basophils, mast cells, and dendritic cells (DCs), have been identified that play specific roles in the pathogenesis of allergic airway inflammation.

The airway epithelial cells act as a barrier and provide protection to the lung from inhaled allergens, pathogens, and other noxious agents in the healthy airways [14,17,18]. When exposed to an antigen, allergen-specific immunoglobulin (Ig)E binds to high-affinity Fcε receptors on the surfaces of basophils and mast cells present in the subepithelial layer of the airways, results in the release of leukotrienes, prostaglandins, and histamine. These mediators will lead to narrowed, constricted airways and further stimulate the recruitment of eosinophils, macrophages, neutrophils, and T lymphocytes [10]. For instance, analysis of allergic airway inflammation using an ovalbumin (OVA) immunization and airway exposure model indicates that eosinophils are required for the development of allergic airway inflammation [19]. Further analysis found that the production of eosinophil-regulated chemokines is required to recruit Th2 cells during the development of allergic asthma by causing prolonged bronchoconstriction and epithelial layer damaging [20,21]. DCs were also demonstrated as necessary and sufficient for the induction of allergic airway inflammation [22]. de Heer HJ et al. [23] found that plasmacytoid DCs were able to control exacerbated airway inflammation through the induction of Tregs. CD11b+ classical type 2 DCs (cDC2s) mediated Th2 priming in response to house dust mite (HDM) and Blomiatropicalis mites [24], leading to eosinophilic airway inflammation, mucus production, and AHR. Upon lung fungal infection with Aspergillus fumigatus, CD11b+ cDC2s promote a Th17 response [25], which contribute to neutrophilic inflammation associated with severe asthma [26]. Therefore, although there is a propensity for type 2 cytokines in the lungs, allergic airway inflammation is a multifactorial disease with a variety of immune cell types as described above.

The effects of MSCs on allergic airway inflammation

MSCs have held great promises in the treatment of allergic airway inflammation not only because of their generative ability to repair/replace the injured lung tissues [27], but also due to their immunomodulatory effect that could increase the resistance of the patients to infections and other forms of allergy [28,29]. Recent research has shown that administration of MSCs is associated with reduced symptoms during severe asthma. Bonfield et al. [30] have emphasized the unique therapeutic potential of MSCs in chronic asthma as MSCs decrease airway inflammation and remodeling in the OVA murine model. MSCs participate in decreasing extracellular matrix deposition by reversing excess collagen deposition and changing hyaluronan levels in OVA-induced model [31]. Li et al. [32] showed the potential of human placenta mesenchymal stem cells in suppressing airway inflammation in asthmatic rats. Sun et al. [33] found that MSCs derived from both iPSCs and bone marrow-derived mesenchymal stem cells (BM-MSCs) protected the mouse from OVA-induced allergic inflammation by inhibiting the majority of allergy-specific pathological changes. The local administration of MSCs was able to attenuate airway AHR, inhibit inflammatory cell infiltration and mucus production in the lung, reduce eosinophil infiltration in the nose, and decrease inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids in the OVA-induced allergic inflammation in mouse [5,29,33–36]. MSCs significantly reduced serum OVA-specific IgE concentration, inhibited expression of Th2 cytokines and elevated level of Treg cytokines [33,36,37]. Monocytes were also recruited by MSCs to secrete IL-10 that lead to reduced airway inflammation and hyper-responsiveness during the process [38]. In addition, Hong et al. [39] demonstrated that MSCs might also have a role in reducing neutrophilic airway inflammation by down-regulating neutrophil chemokine production. By using a mouse model of neutrophilic airway inflammation, Fang et al. [40] investigated the therapeutic potential of iPSC-MSCs in decreasing neutrophilic airway inflammation through the regulation of Th17 cells, suggesting that the iPSC-MSCs could be applied in the therapy for asthma patients with steroid-resistant neutrophilic airway inflammation.

The effects of MSCs on T cells

Th1/Th2 cell imbalance is involved in the pathogenesis of allergic airway inflammation [41]. There are an increasing number of studies showing that MSCs are able to protect the airways from allergen-driven pathology, by which to reduce airway inflammation and allergen-specific IgE [33,34,42]. MSCs possess potent immunoregulatory properties that could modulate the Th1 cytokine responses in benefit of Th2 types [43]. Administration of BM-MSCs effectively reduced allergic symptoms and inflammatory parameters in the mouse model of AR [44]. BM-MSCs were found to migrate to the nasal and lung tissues following intraperitoneal delivery, they ameliorated the airway remodeling and airway inflammation both in the upper and lower airways via the inhibition of Th2 response. Cho et al. found that adipose-derived mesenchymal stem cells (AD-MSCs) ameliorated allergic airway inflammation and improved lung function through the induction of Treg expansion. The induction of Treg by AD-MSCs involves the secretion of soluble factors such as indoleamine 2,3-dioxygenase (IDO), transforming growth factor-β (TGF-β), and prostaglandin E2 (PGE2) and Treg might be involved in the down-regulation of Th2 cytokines and up-regulation of Th1 cytokine production [45,46]. Fu et al. [47] found that iPSC-MSCs were also capable of modulating T-cell phenotypes, which suppressed Th2 phenotype through inducing Treg expansion. MSCs are able to induce Treg cells in vivo to reduce allergen-driven pathology. Multiple Treg dependent and independent mechanisms of therapeutic action are employed by MSCs [34]. Not only the MSCs but also the secretome of the cells showed the capacity of inhibiting allergic airway inflammation. Yu et al. [48] demonstrated that the culture supernatant of AD-MSCs is able to ameliorate allergic airway inflammation via recruitment of CD4+CD25+Foxp3 T cells in the mouse AR model.

MSCs also showed enhancing effects on the proliferation of PBMCs from patients, and the magnitude of proliferative response differs among allergens [49,50]. Fan et al. found that, when iPSC-MSCs were co-cultured with quiescent T cells, iPSC-MSCs promoted the proliferation of resting lymphocytes and activated CD4+ and CD8+ T cells without any additional stimulation. Treg cells were activated at the same time to balance the biased Th1/Th2 cytokine levels [49].

The effects of MSCs on DCs

DCs, the most potent antigen-presenting cells (APCs) in the immune systems, are critical for initiating and regulating immune responses by modulating antigen (Ag)-specific T-cell activation [51]. DCs have been demonstrated to be necessary for the induction of aberrant immunity to allergens or self-antigens in allergic asthma and autoimmune diseases [52]. Many studies have reported that human BM-MSCs inhibit DC differentiation and maturation and induce differentiation of DCs into regulatory DCs [53–56]. Gao et al. found that iPSC-MSCs exert an inhibitory effect on DC differentiation both by producing IL-10 and by direct cell contact, and induce the generation of an IL-10-producing regulatory DC subset in the progress of Lipopolysaccharide-induced maturation mainly via cell–cell contact [57]. Coculture of MSCs with stimulated DCs will result in decreased expression of C-C motif chemokine receptor 7 (CCR7). Similarly, MSC coculture will lead to DC maturation with significantly less migration to C-C motif ligand 19 (CCL19) [58]. MSCs inhibited the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevented the increase of CD40, CD86, and CD83 expression during DC maturation [55]. By inhibiting the activation of mitogen-activated protein kinases (MAPKs) in DCs, MSCs can inhibit the antigen processing and presentation to T cell functions of in vitro cocultured DCs. Furthermore, MSCs are able to down-regulate CCR7 and CD49d, two molecules involved in DC homing to lymphoid organs, in DCs both in vitro and in vivo [59]. Therefore, MSCs play a critical role in the treatment of allergic asthma and allergic rhinitis by regulating DC maturation and differentiation.

The effects of MSCs on epithelial cells

MSCs were found to protect lung epithelial cells exposed to pro-inflammatory cytokines [60–62]. Studies have demonstrated that MSCs and MSC-conditional medium are able to induce repair and protect airway epithelium against cell damage in ex vivo models [63,64]. Furthermore, MSCs reduced apoptosis in pulmonary cell cultures derived from papain-treated mice and in cigarette smoke extract-stimulated endothelial cells [65,66]. This may be due to the engraftment of MSCs in the bronchial epithelium or by paracrine secretions of keratinocyte growth factor (KGF), IL-10, angiopoietin-1, interleukin-1 receptor antagonist, and PGE2 [67]. Islam et al. [67] found that mitochondrial transfer from BM-MSCs to pulmonary alveoli protects against acute lung injury. Li et al. [68] found that iPSC-MSCs decrease the apoptosis of bronchial epithelial cells under hypoxic conditions. Further analysis demonstrated that iPSC-MSCs donate their mitochondria to the dysfunctional mitochondrial epithelial cells, by which they alleviate the asthma inflammation and protect the epithelial cells in the model mouse [29]. Similar results were observed that mitochondrial transfer from MSCs to airway epithelial cells protected against cigarette smoke-induced injury [69]. Therefore, MSCs exert immunomodulative effects on allergic airway inflammation by enhancing epithelial cell proliferation and migration and by reducing epithelial cell apoptosis.

Bronchopulmonary dysplasia (BPD)

In recent years, stem cells have emerged as potential candidates to treat BPD with MSCs being particularly promising [70]. MSCs displayed pleiotropic effects and showed promising results in neonatal rodents in preventing or rescuing lung injury without adverse effects [71]. BM-MSCs showed great potential in migration and homing capacity in BPD models [72,73]. There is a plenty of laboratory evidence demonstrating a protective effect of MSCs in the lung, mostly in hyperoxia-induced lung injury in neonatal rodents [74]. The promising laboratory studies in experimental neonatal lung injury have already led to the first-in-human phase I of allogeneic cord blood-derived MSCs in infants at the risk of developing BPD [75]. On the contrary, Popova et al. [76] showed that the presence of MSC in the tracheal aspirates of preterm infants indicates an increased risk of developing BPD. The role of allogenic MSCs in the pathogenesis BPD is still far away from clear. Although the first MSCs clinical trials in BPD are ongoing, multiple questions still remain.

Cystic fibrosis (CF)

Studies have reported the promising role of stem cells as a potential therapy for CF. MSCs have been proven as an attractive therapeutic modelity in the murine model of CF lung infection and inflammation [77,78]. Allogenic BM-MSCs engrafted into the lungs of cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice; the cells were able to express epithelial phenotypes with CFTR mRNA expression [79,80]. The fight against CF has taken a major step forward. Farrow et al. [81] showed that cells causing the debilitating genetic disorder could be successfully replaced with healthy ones derived from stem cells. In 2017, the first stem cell study in the world for cystic fibrosis opened, allogenic human BM-MSCs from healthy volunteers were infused into a 39-year-old man with CF. The clinical application of stem cells for the treatment of CF certainly warrants further insight into preclinical models, including large animals, organoids, decellularized organs, and lung bioengineering [82,83]. However, engraftment of bone marrow-derived stem cells into the airways is a very inefficient process. Detailed knowledge of the cellular and molecular determinants governing homing to the lung and transformation of MSCs into lung epithelial cells would benefit this process.

Chronic obstructive pulmonary disease (COPD)

Both autologous and allogenic MSCs were widely investigated in the preclinical studies of COPD. Animal model recipients tolerated the injected allogenic MSCs well [84–86]. MSCs were proven able to migrate to the lung and differentiate into type II epithelial cells of the alveoli like cells [87,88]. MSC therapy resulted in the structural repair and functional restoration of the damaged lung in COPD models [60,89,90]. The repair effects of MSCs in the lung with COPD models were mainly caused by multiple paracrine factors secreted by exogenous MSCs. MSCs were also able to replace the damaged structures and contribute to the restoration of lung function [84]. However, the engraftment and survival rate of allogenic MSCs were very low in COPD models [80,91]. Therefore, the successful preclinical studies have not led to the success of clinical trials so far [84]. The source and status of MSCs, dosage issues, patient scales as well as the stage of the disease might contribute to the conflicting results between preclinical studies and clinical trials. Great efforts must be made to figure out the mechanisms that will lead toward a curing solution for COPD patients.

The mechanism of MSC action on airway inflammation

Human MSCs express low levels of major histocompatibility complex (MHC) class I molecules and have no MHC class II molecules or costimulatory molecules, including CD40, CD40L, CD80, and CD86 on cellular surface, which make the cells hypoimmunogenic [92]. Research found that MSCs do not provoke an immunological response even if the MHC class I and MHC class II molecules were up-regulated by the presence of Interferon γ (IFN-γ) [93,94]. Also, the costimulatory molecules are tightly regulated by the inhibitory molecules on MSCs when up-regulated under inflammatory conditions [95,96]. Khattar et al. [97] found that transcriptional reactivation of telomerase reverse transcriptase (TERT) expression in MSCs may directly control immunomodulation related protein synthesis by regulating tRNA gene expression. And the mechanisms of activating transcription from TERT promoters in stem cells could be vastly different depending on the status and microenvironment of the cells [98]. Moreover, MSCs are able to inhibit T-lymphocyte proliferation in mixed lymphocyte culture or in the presence of activators, such as IL-2 and phytohemagglutinin (PHA) [99]. Whereas MSCs were found to support T-cell survival and proliferation when these cells are not activated [49,100,101]. Some studies have shown that MSCs reduced the expression of activation markers on the lymphocytes [102,103], while others found no expression changes of these markers [104,105]. Therefore, the mechanisms involved in the immunomodulatory effects of MSCs on immune cells include different cell–cell contact, soluble factors, genomic regulation, nuclear factor κB (NF-κB) signaling pathway and mitochondrial transfer etc. (see Figure 1 for a schematic overview)

Schematic illustration of mechanisms underlying the MSCs immunomodulatory effects

Figure 1
Schematic illustration of mechanisms underlying the MSCs immunomodulatory effects

MSCs potentially modulate the immune cells (T cells and dendritic cells) and epithelial cells, which are involved in the airway inflammation. The MSCs function their modulatory effects via cell–cell contact, (anti)-inflammatory cytokines and chemokines, genomic regulation, and mitochondrial transfer, to improve lung tissue homeostasis.

Figure 1
Schematic illustration of mechanisms underlying the MSCs immunomodulatory effects

MSCs potentially modulate the immune cells (T cells and dendritic cells) and epithelial cells, which are involved in the airway inflammation. The MSCs function their modulatory effects via cell–cell contact, (anti)-inflammatory cytokines and chemokines, genomic regulation, and mitochondrial transfer, to improve lung tissue homeostasis.

Cell–cell contact

MSCs have been demonstrated as expressing integrins (α1-6, αV, and β1-4), intercellular adhesion molecules (ICAM-1, ICAM-2), vascular cell adhesion protein (VCAM)-1, CD72, and CD58 (LFA-3) on their surfaces, which allow them to modulate both autologous and allogeneic T lymphocytes via cell-to-cell contact in vitro [99,106]. Ren et al. demonstrated that ICAM-1 and VCAM-1 on MSCs positively correlate with the immunomodulatory effects of MSCs toward various subtypes of T cells [107,108]. The immunomodulatory effects of MSCs can be significantly reversed by the genetic deletion or functional blocking of adhesion molecules in the cells [109]. In addition, studies claimed that cell–cell contact is necessary for the MSC-mediated inhibition of allogeneic Th17 differentiation, and the expression of programmed death-1 (PD-1) ligand on the surface of MSCs is critical for this [110,111]. Similarly, galectins were found to be constitutively expressed on MSCs and mediated the immunomodulatory effects of MSCs [112]. For instance, CD4+ and CD8+ T cell proliferation were inhibited by galectin-1 and galectin-3 [112,113]. And the expression of galectin-9 was found to be associated with the anti-proliferative effects that MSCs have on T cells [114].

Soluble factors

Although cell–cell contact has been demonstrated as being necessary for the immunodulatory effects of MSCs, transwell membrane experiments showed that MSCs can also exert their immunomodulatory functions through releasing soluble factors [93,99]. The production of suppressive soluble factors is dependent on a cross-talk between MSCs and activated immune cells, inflammatory cytokines secreted by antigen-presenting cells and T cells, including interferon-γ (IFN-γ), IL-1α, IL-1β, and tumor necrosis factor-α (TNF-α) are required for the immunomodulatory activities of MSCs. Researchers found that the use of supernatants from MSCs culture is not enough for T-cell suppression [115]. Whereas the supernatants from MSC-activated T-cell coculture system can suppress T-cell proliferation [92,116]. It suggests that the immunomodulatory effects of MSCs rely on a combination of the complex interplay between soluble factors and specific inflammatory microenvironment.

Many MSC-derived soluble factors have been identified to be associated with the immunomodulatory effects, such as hepatic growth factor (HGF), TGF-β [99], nitric oxide (NO) [117], PGE2 [118], IDO [119], IL-6 [120], and IL-10 [121] etc. These soluble factors are able to ablate the recruitment, activation, and maturation of DCs in the lung and the reactivation of Th2-cytokine–producing CD4+ Th2 cells, by which to ameliorate allergic airway inflammation. The immunomodulatory effects could be monitored by controlling the paracrine effects of MSCs. For example, rap 1 is a key regulator for regulating inflammation [122,123]. Zhang et al. [124] revealed the reduction of pro-inflammatory paracrine cytokines in rap-inhibited MSCs for the MSC-based treatments. Since they have been revealed as a potential link between physiological cues and human ailments [125], nuclear, casein kinase and cyclin-dependent kinase substrate (NUCKS) were also found to be involved in the metabolism and paracrine effects of human MSCs [126,127]. Zhang et al. [128] presented up-regulated paracrine effects in NUCKS knockout MSCs. In addition, it is worth noticing that there are some well acknowledged differences between MSCs derived from different species, which should be considered carefully before interpreting the preclinical data. For instance, human MSCs suppress T-cell proliferation by IDO production, while inducible nitric oxide synthase (iNOS) is employed by mouse MSCs to exert the same function [99,108,129].

Noncoding RNAs

Researches have shown that administration of MSCs after allergen challenge resulted in changes in gene expression in allergic airway inflammation. Tang et al. [130] identified different miRNA and mRNA profiles after asthma induction and BM-MSC treatment, and the miR-21/Acvr2a axis was figured out as an important mechanism for the induction of asthmatic inflammation. In addition, miR-21 was also found mediating the protective effects of iPSC-MSCs in human bronchial epithelial cells under hypoxic conditions [68]. mRNA Ccl11, Ccl24, Il13, Il33, and Ear11 were found being involved in the process of human embryonic stem cell derived MSC immunomodulation in airway allergic inflammation [5]. Furthermore, Wang et al. [131] examined the long noncoding RNA (lncRNA) expression after the induction of asthma, and the differentially expressed lncRNAs after iPSC-MSC treatment. lncRNAsMM9LINCRNAEXON12105+ and AK089315 were finally emphasized as the potential regulators of allergy and the targets of iPSC-MSC treatment. By using various knockout mice, researchers could clearly investigate the genes involved in the MSC immunomodulatory process.

Nuclear factor κB (NF-κB)

MSCs have been demonstrated to sense the inflammatory mediators such as IFN-γ, TNF-α, IL-1, chemokines and leukotrienes, they are able to activate NF-κB to promote the immunomodulatory effects in the inflammatory microenvironment [132–134]. For instance, it has been demonstrated that TNF-α released by activated T cells binds to TNF-R1 on MSCs, activating the NF-κB pathway and contributing to the immunomodulatory effects of MSCs [135–138]. Studies have shown that MSCs inhibit the proliferation of cytotoxic T lymphocytes by B7-H4, which can inhibit the NF-κβ activities [139]. Saldanha-Araujo et al. [140] demonstrated that MSCs are able to induce a shift of NF-κB signaling in T-lymphocytes from canonical to noncanonical, by which they suppress the activation of the T-lymphocytes in the coculture system. Whereas Fan et al. [49] found that MSCs up-regulate the proliferation and activation of quiescent T cells of AR patients via NF-κB signaling pathway. In addition, MSCs promote the differentiation of monocytes to M2 phenotype macrophages through NF-κB and signal transducer and activator of transcription 3 (STAT-3) pathways in the presence of IDO [141–143]. Human MSCs have also been proven to activate peritoneal macrophages via toll-like receptor 2 (TLR2) NF-κB signaling by secreting TNF-stimulated gene 6 (TSG6), which regulates TLR2 NF-κB signaling [144]. Therefore, NF-κB is tightly involved in the immunomodulatory function of MSCs.

Mitochondrial transfer

Mitochondrial transfer is another significant application of MSCs in the treatment of diseases. It has been well-demonstrated that MSCs can deliver function-normal mitochondria to the donor cells or tissues to alleviate the oxidative stresses and cell apoptosis in cardiac diseases with mitochondria damage [145,146]. Recent research has also presented the MSCs-mediated mitochondrial transfer in lung disease treatments. BM-MSCs have shown positive effects in treating mouse models of acute lung injury and allergic airway inflammation via mitochondrial transfer [67,147]. Li et al. [69] presented that MSCs derived from iPSCs protected airway epithelial cells from smoke-caused mitochondria damage by mitochondria transfer, which occurs via the tunneling of nanotubes (TNTs). Yao et al. [29] further demonstrated that iPSC-MSCs attenuate asthma inflammation and protect epithelial cells by transferring their mitochondria via TNTs. Li et al. [28] also presented that mitochondrial transfer prevented the oxidative stresses caused by the damaged mitochondria in the airways. In addition, the transferred mitochondria can alleviate the inflammatory responses of the receptors [29,67]. Several known mechanisms have been revealed for the MSCs mediated mitochondrial transfer in lung disease treatments. Mitochondrial Rho GTPase 1 (MIRO1) was confirmed playing a critical role in the regulation of MSC mitochondrial transfer by MIRO1 overexpression in iPSC-MSCs [147,148]. The microtubule motor protein kinesin family member 5B (KIF5B) is considered to be a regulator of mitochondrial transfer [149]. Furthermore, connexin 43 (CX43) has been found as vital for regulating the TNT formation and mitochondrial transfer efficiency of iPSC-MSCs. Overexpression of CX43 in iPSC-MSCs enhanced the TNT formation between iPSC-MSCs and damaged epithelial cells, the mitochondrial transfer efficiency was also significantly increased. Also, silencing CX43 reduced TNT formation and the immunomodulatory effects of iPSC-MSCs during allergic airway inflammation [29].

Promises and challenges

Current advantages of MSC immunomodulation eventually would lead to a growing exploration of MSCs in clinical trials of allergic airway inflammation. Clinical trials have clearly assessed the safety and feasibility of using MSC treatment for the patients affected by moderate or severe acute respiratory distress syndrome and idiopathic pulmonary fibrosis [150]. There are increasing number of completed and ongoing registered studies examining the effects of MSCs on allergic airway inflammation in human clinical trials on ClinicalTrials.gov database. The number of registered clinical trials testing MSCs has become to 905 internationally, which was only 402 in 2015. However, the major outcomes of clinical trials of MSCs in respiratory disorders have fallen far short of the theoretical potential of these cells in preclinical studies [133]. There is insufficient clinical benefit apparent in early efficacy studies to warrant further commitment of relatively scarce finances [151].

There are still obstacles to be overcome before MSCs becoming realistic in clinics, and the cure to inflammatory airway disorders remains elusive. There is more and more evidence demonstrating the potential of MSC-derived extracellular vesicles (EVs) in respiratory diseases such as asthma [152–155]. However, MSCs and their derived EVs were observed provoking different effects and lung mechanics [154]. More information about the secretome of MSCs is needed before use in therapy. In-depth studies of the mechanisms of MSCs in inflammatory airway disorders are still needed, which to cover cell trafficking, clinical ethics, regulations, and practices in stem cell therapies.

On the other hand, it is still unclear how to develop high-quality, clinical-grade cell products. It is difficult for quality control because different manufacturers produce the products at different sites probably according to different protocols. In addition, even the consistency of the products from the same site is hard to maintain due to problems with the source, batch or derived tissue of the MSCs. It is better for patients to utilize their own stem cell reserves to create robust health and heal from diseases. Therefore, there are still meaningful differences in MSC cell preparation, fitness, and functionality due to the MSC tissue source, culture methods, and expansion levels. It is clear that MSCs are very promising with numerous potential benefits in the treatment of inflammatory airway disorders; however, there are challenges that have to be overcome before stem cells can be safely, effectively, and routinely used in the clinical setting.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by grants from NSFC for Excellent Young Scholars [81322012 to (Q.-L.F.]; NSFC [81373174, 81471832, 81671882 and 81770984]; the key grant from the Science and Technology Foundation of Guangdong Province of China [2015B020225001]; and the Natural Science Foundation of Guangdong Province [2014A030313051, 2016A030308017 and 2017A030313105].

Author Contribution

X.-L.F., Z.Z., C.Y.M. wrote the manuscript; Q.-L.F. designed and wrote the manuscript.

Abbreviations

     
  • AD-MSC

    adipose-derived mesenchymal stem cell

  •  
  • Ag

    antigen

  •  
  • AHR

    airway hyper-responsiveness

  •  
  • APC

    antigen-presenting cell

  •  
  • AR

    allergic rhinitis

  •  
  • BM-MSC

    bone marrow-derived mesenchymal stem cell

  •  
  • BPD

    bronchopulmonary dysplasia

  •  
  • CCL19

    C-C motif ligand 19

  •  
  • CCR7

    C-C motif chemokine receptor 7

  •  
  • CD

    cluster of differentiation

  •  
  • cDC2

    classical type 2 DC

  •  
  • CF

    cystic fibrosis

  •  
  • CFTR

    cystic fibrosis transmembrane conductance regulator

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • CX43

    connexin 43

  •  
  • DC

    dendritic cell

  •  
  • ESC

    embryonic stem cell

  •  
  • EV

    extracellular vesicle

  •  
  • HGF

    hepatic growth factor

  •  
  • HDM

    house dust mite

  •  
  • IDO

    indoleamine 2,3-dioxygenase

  •  
  • Ig

    immunoglobulin

  •  
  • IFN-γ

    interferon-γ

  •  
  • IL

    interleukin

  •  
  • iNOS

    inducible nitric oxide synthase

  •  
  • iPSC

    induced pluripotent stem cell

  •  
  • KGF

    keratinocyte growth factor

  •  
  • KIF5B

    kinesin family member 5B

  •  
  • lncRNA

    long noncoding RNA

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MIRO1

    mitochondrial Rho GTPase 1

  •  
  • MSC

    mesenchymal stem cell

  •  
  • NF-κB

    nuclear factor κB

  •  
  • NO

    nitric oxide

  •  
  • NUCKS

    nuclear, casein kinase and cyclin-dependent kinase substrate

  •  
  • OVA

    ovalbumin

  •  
  • PGE2

    prostaglandin E2

  •  
  • STAT-3

    signal transducer and activator of transcription 3

  •  
  • TGF-β

    transforming growth factor-β

  •  
  • Th

    T-helper

  •  
  • TLR2

    toll-like receptor 2

  •  
  • TNF-α

    tumor necrosis factor-α

  •  
  • TNT

    tunneling of nanotube

  •  
  • TSG6

    TNF-stimulated gene 6

References

References
1.
Ullah
I.
,
Subbarao
R.B.
and
Rho
G.J.
(
2015
)
Human mesenchymal stem cells - current trends and future prospective
.
Biosci. Rep.
35
,
[PubMed]
2.
Horwitz
E.M.
,
Le Blanc
K.
,
Dominici
M.
,
Mueller
I.
,
Slaper-Cortenbach
I.
,
Marini
F.C.
et al.
(
2005
)
Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement
.
Cytotherapy
7
,
393
395
[PubMed]
3.
Lian
Q.
,
Zhang
Y.
,
Liang
X.
,
Gao
F.
and
Tse
H.-F.
(
2016
)
Directed differentiation of human-induced pluripotent stem cells to mesenchymal stem cells
.
Methods Mol. Biol.
1416
,
289
298
4.
Soontararak
S.
,
Chow
L.
,
Johnson
V.
,
Coy
J.
,
Wheat
W.
,
Regan
D.
et al.
(
2018
)
Mesenchymal stem cells (MSC) derived from induced pluripotent stem cells (iPSC) equivalent to adipose-derived MSC in promoting intestinal healing and microbiome normalization in mouse inflammatory bowel disease model
.
Stem Cells Transl. Med.
7
,
456
467
[PubMed]
5.
Lin
Y.D.
,
Fan
X.L.
,
Zhang
H.
,
Fang
S.B.
,
Li
C.L.
,
Deng
M.X.
et al.
(
2018
)
The genes involved in asthma with the treatment of human embryonic stem cell-derived mesenchymal stem cells
.
Mol. Immunol.
95
,
47
55
[PubMed]
6.
Keating
A.
(
2008
)
How do mesenchymal stromal cells suppress T cells?
Cell Stem Cell
2
,
106
108
[PubMed]
7.
Wei
W.
,
Huang
Y.
,
Li
D.
,
Gou
H.F.
and
Wang
W.
(
2018
)
Improved therapeutic potential of MSCs by genetic modification
.
Gene Ther.
,
25
,
538
547
8.
Ding
Y.
,
Liang
X.
,
Zhang
Y.
,
Yi
L.
,
Shum
H.C.
,
Chen
Q.
et al.
(
2018
)
Rap1 deficiency-provoked paracrine dysfunction impairs immunosuppressive potency of mesenchymal stem cells in allograft rejection of heart transplantation
.
Cell Death Dis.
9
,
386
9.
Weiss
D.J.
,
Bates
J.H.
,
Gilbert
T.
,
Liles
W.C.
,
Lutzko
C.
,
Rajagopal
J.
et al.
(
2013
)
Stem cells and cell therapies in lung biology and diseases: conference report
.
Ann. Am. Thorac Soc.
10
,
S25
S44
[PubMed]
10.
Broide
D.H.
(
2001
)
Molecular and cellular mechanisms of allergic disease
.
J. Allergy Clin. Immunol.
108
,
S65
S71
[PubMed]
11.
Agrawal
D.K.
and
Shao
Z.
(
2010
)
Pathogenesis of allergic airway inflammation
.
Curr. Allergy Asthma Rep.
10
,
39
48
[PubMed]
12.
Elias
J.A.
,
Lee
C.G.
,
Zheng
T.
,
Ma
B.
,
Homer
R.J.
and
Zhu
Z.
(
2003
)
New insights into the pathogenesis of asthma
.
J. Clin. Invest.
111
,
291
297
[PubMed]
13.
Wills-Karp
M.
,
Luyimbazi
J.
,
Xu
X.
,
Schofield
B.
,
Neben
T.Y.
,
Karp
C.L.
et al.
(
1998
)
Interleukin-13: central mediator of allergic asthma
.
Science
282
,
2258
2261
[PubMed]
14.
Anagnostopoulou
P.
,
Dai
L.
,
Schatterny
J.
,
Hirtz
S.
,
Duerr
J.
and
Mall
M.A.
(
2010
)
Allergic airway inflammation induces a pro-secretory epithelial ion transport phenotype in mice
.
Eur. Respir. J.
36
,
1436
1447
[PubMed]
15.
Pepper
A.N.
,
Renz
H.
,
Casale
T.B.
and
Garn
H.
(
2017
)
Biologic Therapy and Novel Molecular Targets of Severe Asthma
.
J. Allergy Clin Immunol. Pract.
5
,
909
916
[PubMed]
16.
Garn
H.
(
2018
)
Is 9 more than 2 also in allergic airway inflammation?
J. Allergy Clin. Immunol.
141
,
2024
2026
[PubMed]
17.
Mall
M.A.
(
2008
)
Role of cilia, mucus, and airway surface liquid in mucociliary dysfunction: lessons from mouse models
.
J. Aerosol. Med. Pulm Drug Deliv.
21
,
13
24
[PubMed]
18.
Wanner
A.
,
Salathe
M.
and
O’Riordan
T.G.
(
1996
)
Mucociliary clearance in the airways
.
Am. J. Respir. Crit. Care Med.
154
,
1868
1902
[PubMed]
19.
Lee
J.J.
,
Dimina
D.
,
Macias
M.P.
,
Ochkur
S.I.
,
McGarry
M.P.
,
O’Neill
K.R.
et al.
(
2004
)
Defining a link with asthma in mice congenitally deficient in eosinophils
.
Science
305
,
1773
1776
[PubMed]
20.
Walsh
E.R.
,
Sahu
N.
,
Kearley
J.
,
Benjamin
E.
,
Kang
B.H.
,
Humbles
A.
et al.
(
2008
)
Strain-specific requirement for eosinophils in the recruitment of T cells to the lung during the development of allergic asthma
.
J. Exp. Med.
205
,
1285
1292
[PubMed]
21.
Jacobsen
E.A.
,
Ochkur
S.I.
,
Pero
R.S.
,
Taranova
A.G.
,
Protheroe
C.A.
,
Colbert
D.C.
et al.
(
2008
)
Allergic pulmonary inflammation in mice is dependent on eosinophil-induced recruitment of effector T cells
.
J. Exp. Med.
205
,
699
710
[PubMed]
22.
Conejero
L.
,
Khouili
S.C.
,
Martínez-Cano
S.
,
Izquierdo
H.M.
,
Brandi
P.
and
Sancho
D.
(
2017
)
Lung CD103+ dendritic cells restrain allergic airway inflammation through IL-12 production
.
JCI Insight
2
,
e90420
[PubMed]
23.
de Heer
H.J.
,
Hammad
H.
,
Soullie
T.
,
Hijdra
D.
,
Vos
N.
,
Willart
M.A.
et al.
(
2004
)
Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen
.
J. Exp. Med.
200
,
89
98
[PubMed]
24.
Zhou
Q.
,
Ho
A.W.
,
Schlitzer
A.
,
Tang
Y.
,
Wong
K.H.
,
Wong
F.H.
et al.
(
2014
)
GM-CSF-licensed CD11b+ lung dendritic cells orchestrate Th2 immunity to Blomia tropicalis
.
J. Immunol.
193
,
496
509
[PubMed]
25.
Schlitzer
A.
,
McGovern
N.
,
Teo
P.
,
Zelante
T.
,
Atarashi
K.
,
Low
D.
et al.
(
2013
)
IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses
.
Immunity
38
,
970
983
[PubMed]
26.
Lambrecht
B.N.
and
Hammad
H.
(
2015
)
The immunology of asthma
.
Nat. Immunol.
16
,
45
56
[PubMed]
27.
Royce
S.G.
,
Rele
S.
,
Broughton
B.R.S.
,
Kelly
K.
and
Samuel
C.S.
(
2017
)
Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease
.
FASEB J.
31
,
4168
4178
[PubMed]
28.
Li
X.
,
Michaeloudes
C.
,
Zhang
Y.
,
Wiegman
C.H.
,
Adcock
I.M.
,
Lian
Q.
et al.
(
2018
)
Mesenchymal stem cells alleviate oxidative stress–induced mitochondrial dysfunction in the airways
.
J. Allergy Clin. Immunol.
141
,
1634.e5
1645.e5
[PubMed]
29.
Yao
Y.
,
Fan
X.L.
,
Jiang
D.
,
Zhang
Y.
,
Li
X.
,
Xu
Z.B.
et al.
(
2018
)
Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation
.
Stem Cell Rep.
11
,
1120
1135
[PubMed]
30.
Bonfield
T.
,
Sutton
M.
,
Lennon
D.
and
Caplan
A.
(
2015
)
Mesenchymal stem cells: new directions in treating asthma
.
J. Immunol.
194
[PubMed]
31.
Goldstein
B.D.
,
Lauer
M.E.
,
Caplan
A.I.
and
Bonfield
T.L.
(
2017
)
Chronic asthma and Mesenchymal stem cells: Hyaluronan and airway remodeling
.
J. Inflammation
14
,
32.
Li
Y.
,
Qu
T.
,
Tian
L.
,
Han
T.
,
Jin
Y.
and
Wang
Y.
(
2018
)
Human placenta mesenchymal stem cells suppress airway inflammation in asthmatic rats by modulating Notch signaling
.
Mol. Med. Rep.
17
,
5336
5343
[PubMed]
33.
Sun
Y.Q.
,
Deng
M.X.
,
He
J.
,
Zeng
Q.X.
,
Wen
W.
,
Wong
D.S.
et al.
(
2012
)
Human pluripotent stem cell-derived mesenchymal stem cells prevent allergic airway inflammation in mice
.
Stem Cells
30
,
2692
2699
[PubMed]
34.
Kavanagh
H.
and
Mahon
B.P.
(
2011
)
Allogeneic mesenchymal stem cells prevent allergic airway inflammation by inducing murine regulatory T cells
.
Allergy
66
,
523
531
[PubMed]
35.
Mohammadian
M.
,
Boskabady
M.H.
,
Kashani
I.R.
,
Jahromi
G.P.
,
Omidi
A.
,
Nejad
A.K.
et al.
(
2016
)
Effect of bone marrow derived mesenchymal stem cells on lung pathology and inflammation in ovalbumin-induced asthma in mouse
.
Iran J. Basic Med. Sci.
19
,
55
63
[PubMed]
36.
Chuang
Y.C.
,
Liou
C.W.
,
Chen
S.D.
,
Wang
P.W.
,
Chuang
J.H.
,
Tiao
M.M.
et al.
(
2017
)
Mitochondrial Transfer from Wharton’s Jelly Mesenchymal Stem Cell to MERRF Cybrid Reduces Oxidative Stress and Improves Mitochondrial Bioenergetics
.
Oxid Med. Cell Longev.
2017
,
5691215
[PubMed]
37.
Habibian
R.
,
Delirezh
N.
and
Farshid
A.A.
(
2018
)
The effects of bone marrow-derived mesenchymal stem cells on ovalbumin-induced allergic asthma and cytokine responses in mice
.
Iran J. Basic Med. Sci.
21
,
483
488
[PubMed]
38.
Takeda
K.
,
Webb
T.L.
,
Ning
F.K.
,
Shiraishi
Y.
,
Regan
D.P.
,
Chow
L.
et al.
(
2018
)
Mesenchymal Stem Cells Recruit CCR2(+) Monocytes To Suppress Allergic Airway Inflammation
.
J. Immunol.
200
,
1261
1269
[PubMed]
39.
Hong
G.H.
,
Kwon
H.S.
,
Lee
K.Y.
,
Ha
E.H.
,
Moon
K.A.
,
Kim
S.W.
et al.
(
2017
)
hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma
.
Exp. Mol. Med.
49
,
e288
[PubMed]
40.
Fang
S.B.
,
Zhang
H.Y.
,
Jiang
A.Y.
,
Fan
X.L.
,
Lin
Y.D.
,
Li
C.L.
et al.
(
2018
)
Human iPSC-MSCs prevent steroid-resistant neutrophilic airway inflammation via modulating Th17 phenotypes
.
Stem. Cell Res. Ther.
9
,
147
[PubMed]
41.
Mazzarella
G.
,
Bianco
A.
,
Catena
E.
,
De Palma
R.
and
Abbate
G.F.
(
2000
)
Th1/Th2 lymphocyte polarization in asthma
.
Allergy
55
,
6
9
[PubMed]
42.
Gao
F.
,
Chiu
S.M.
,
Motan
D.A.
,
Zhang
Z.
,
Chen
L.
,
Ji
H.L.
et al.
(
2016
)
Mesenchymal stem cells and immunomodulation: current status and future prospects
.
Cell Death Dis
7
,
e2062
[PubMed]
43.
Salek Farrokhi
A.
,
Zarnani
A.H.
and
Moazzeni
S.M.
(
2018
)
Mesenchymal stem cells therapy protects fetuses from resorption and induces Th2 type cytokines profile in abortion prone mouse model
.
Transpl. Immunol.
47
,
26
31
[PubMed]
44.
Zhao
N.
,
Liu
Y.
,
Liang
H.
and
Jiang
X.
(
2016
)
Bone marrow-derived mesenchymal stem cells reduce immune reaction in a mouse model of allergic rhinitis
.
Am. J. Transl. Res.
8
,
5628
5636
[PubMed]
45.
Cho
K.S.
,
Park
M.K.
,
Kang
S.A.
,
Park
H.Y.
,
Hong
S.L.
,
Park
H.K.
et al.
(
2014
)
Adipose-derived stem cells ameliorate allergic airway inflammation by inducing regulatory T cells in a mouse model of asthma
.
Mediators Inflamm.
2014
,
436476
[PubMed]
46.
Dai
R.
,
Yu
Y.
,
Yan
G.
,
Hou
X.
,
Ni
Y.
and
Shi
G.
(
2018
)
Intratracheal administration of adipose derived mesenchymal stem cells alleviates chronic asthma in a mouse model
.
BMC Pulm. Med.
18
,
131
[PubMed]
47.
Fu
Q.L.
,
Chow
Y.Y.
,
Sun
S.J.
,
Zeng
Q.X.
,
Li
H.B.
,
Shi
J.B.
et al.
(
2012
)
Mesenchymal stem cells derived from human induced pluripotent stem cells modulate T-cell phenotypes in allergic rhinitis
.
Allergy
67
,
1215
1222
[PubMed]
48.
Yu
H.S.
,
Park
M.K.
,
Kang
S.A.
,
Cho
K.S.
,
Mun
S.J.
and
Roh
H.J.
(
2017
)
Culture supernatant of adipose stem cells can ameliorate allergic airway inflammation via recruitment of CD4(+)CD25(+)Foxp3 T cells
.
Stem Cell Res. Ther.
8
,
8
[PubMed]
49.
Fan
X.L.
,
Zeng
Q.X.
,
Li
X.
,
Li
C.L.
,
Xu
Z.B.
,
Deng
X.Q.
et al.
(
2018
)
Induced pluripotent stem cell-derived mesenchymal stem cells activate quiescent T cells and elevate regulatory T cell response via NF-kappaB in allergic rhinitis patients
.
Stem Cell Res. Ther.
9
,
170
[PubMed]
50.
Desai
M.
,
Capitle
E.
,
Patel
S.
and
Rameshwar
P.
(
2011
)
Effects of mesenchymal stem cells on pollen-induced lymphocyte proliferation in subjects with allergic rhinitis: implications of stem cell activity on immune response to pollen
.
J. Allergy Clin. Immunol.
127
,
AB99
51.
Banchereau
J.
and
Steinman
R.M.
(
1998
)
Dendritic cells and the control of immunity
.
Nature
392
,
245
252
[PubMed]
52.
van Helden
M.J.
and
Lambrecht
B.N.
(
2013
)
Dendritic cells in asthma
.
Curr. Opin. Immunol.
25
,
745
754
[PubMed]
53.
Jiang
X.X.
,
Zhang
Y.
,
Liu
B.
,
Zhang
S.X.
,
Wu
Y.
,
Yu
X.D.
et al.
(
2005
)
Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells
.
Blood
105
,
4120
4126
[PubMed]
54.
Spaggiari
G.M.
,
Abdelrazik
H.
,
Becchetti
F.
and
Moretta
L.
(
2009
)
MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2
.
Blood
113
,
6576
6583
[PubMed]
55.
Zhang
W.
,
Ge
W.
,
Li
C.
,
You
S.
,
Liao
L.
,
Han
Q.
et al.
(
2004
)
Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells
.
Stem Cells Dev.
13,
263
271
56.
Beyth
S.
,
Borovsky
Z.
,
Mevorach
D.
,
Liebergall
M.
,
Gazit
Z.
,
Aslan
H.
et al.
(
2005
)
Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness
.
Blood
105
,
2214
2219
[PubMed]
57.
Gao
W.X.
,
Sun
Y.Q.
,
Shi
J.
,
Li
C.L.
,
Fang
S.B.
,
Wang
D.
et al.
(
2017
)
Effects of mesenchymal stem cells from human induced pluripotent stem cells on differentiation, maturation, and function of dendritic cells
.
Stem Cell Res. Ther.
8
,
48
[PubMed]
58.
English
K.
,
Barry
F.P.
and
Mahon
B.P.
(
2008
)
Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation
.
Immunol. Lett.
115
,
50
58
[PubMed]
59.
Chiesa
S.
,
Morbelli
S.
,
Morando
S.
,
Massollo
M.
,
Marini
C.
,
Bertoni
A.
et al.
(
2011
)
Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells
.
Proc. Natl. Acad. Sci. U.S.A.
108
,
17384
17389
[PubMed]
60.
Huh
J.W.
,
Kim
S.Y.
,
Lee
J.H.
,
Lee
J.S.
,
Van Ta
Q.
,
Kim
M.
et al.
(
2011
)
Bone marrow cells repair cigarette smoke-induced emphysema in rats
.
Am. J. Physiol. Lung Cell. Mol. Physiol.
301
,
L255
L266
[PubMed]
61.
Li
J.
,
Huang
S.
,
Zhang
J.
,
Feng
C.
,
Gao
D.
,
Yao
B.
et al.
(
2016
)
Mesenchymal stem cells ameliorate inflammatory cytokine-induced impairment of AT-II cells through a keratinocyte growth factor-dependent PI3K/Akt/mTOR signaling pathway
.
Mol. Med. Rep.
13
,
3755
3762
[PubMed]
62.
Broekman
W.
,
Amatngalim
G.D.
,
de Mooij-Eijk
Y.
,
Oostendorp
J.
,
Roelofs
H.
,
Taube
C.
et al.
(
2016
)
TNF-alpha and IL-1beta-activated human mesenchymal stromal cells increase airway epithelial wound healing in vitro via activation of the epidermal growth factor receptor
.
Respir. Res.
17
,
3
[PubMed]
63.
Akram
K.M.
,
Samad
S.
,
Spiteri
M.A.
and
Forsyth
N.R.
(
2013
)
Mesenchymal stem cells promote alveolar epithelial cell wound repair in vitro through distinct migratory and paracrine mechanisms
.
Respir. Res.
14
,
9
[PubMed]
64.
Yew
T.L.
,
Hung
Y.T.
,
Li
H.Y.
,
Chen
H.W.
,
Chen
L.L.
,
Tsai
K.S.
et al.
(
2011
)
Enhancement of wound healing by human multipotent stromal cell conditioned medium: the paracrine factors and p38 MAPK activation
.
Cell Transplant.
20
,
693
706
[PubMed]
65.
Zhen
G.
,
Xue
Z.
,
Zhao
J.
,
Gu
N.
,
Tang
Z.
,
Xu
Y.
et al.
(
2010
)
Mesenchymal stem cell transplantation increases expression of vascular endothelial growth factor in papain-induced emphysematous lungs and inhibits apoptosis of lung cells
.
Cytotherapy
12
,
605
614
[PubMed]
66.
Guan
X.-J.
,
Song
L.
,
Han
F.-F.
,
Cui
Z.-L.
,
Chen
X.
,
Guo
X.-J.
et al.
(
2013
)
Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF–VEGF receptors
.
J. Cell. Biochem.
114
,
323
335
[PubMed]
67.
Islam
M.N.
,
Das
S.R.
,
Emin
M.T.
,
Wei
M.
,
Sun
L.
,
Westphalen
K.
et al.
(
2012
)
Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury
.
Nat. Med.
18
,
759
765
[PubMed]
68.
Li
C.L.
,
Xu
Z.B.
,
Fan
X.L.
,
Chen
H.X.
,
Yu
Q.N.
,
Fang
S.B.
et al.
(
2018
)
microRNA-21 mediates the protective effects of mesenchymal stem cells derived from iPSCs to human bronchial epithelial cell injury under hypoxia
.
Cell Transplant.
27
,
571
583
69.
Li
X.
,
Zhang
Y.
,
Yeung
S.C.
,
Liang
Y.
,
Liang
X.
,
Ding
Y.
et al.
(
2014
)
Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage
.
Am. J. Respir. Cell Mol. Biol.
51
,
455
465
[PubMed]
70.
Mueller
M.
and
Kramer
B.W.
(
2017
)
Stem cells and bronchopulmonary dysplasia - the five questions: Which cells, when, in which dose, to which patients via which route?
Paediatr. Respir. Rev.
24
,
54
59
[PubMed]
71.
Ee
M.T.
and
Thebaud
B.
(
2018
)
Therapeutic potential of stem cells for bronchopulmonary dysplasia: “It’s about time” or “Not so fast”?
Curr. Pediatr. Rev.
14
,
227
238
[PubMed]
72.
Aslam
M.
,
Baveja
R.
,
Liang
O.D.
,
Fernandez-Gonzalez
A.
,
Lee
C.
,
Mitsialis
S.A.
et al.
(
2009
)
Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease
.
Am. J. Respir. Crit. Care Med.
180
,
1122
1130
[PubMed]
73.
Zhang
X.
,
Wang
H.
,
Shi
Y.
,
Peng
W.
,
Zhang
S.
,
Zhang
W.
et al.
(
2012
)
Role of bone marrow-derived mesenchymal stem cells in the prevention of hyperoxia-induced lung injury in newborn mice
.
Cell Biol. Int.
36
,
589
594
[PubMed]
74.
Mobius
M.A.
and
Thebaud
B.
(
2016
)
Cell therapy for bronchopulmonary dysplasia: promises and perils
.
Paediatr. Respir. Rev.
20
,
33
41
[PubMed]
75.
Chang
Y.S.
,
Ahn
S.Y.
,
Yoo
H.S.
,
Sung
S.I.
,
Choi
S.J.
,
Oh
W.I.
et al.
(
2014
)
Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial
.
J. Pediatr.
164
,
966e6
972e6
[PubMed]
76.
Popova
A.P.
,
Bozyk
P.D.
,
Bentley
J.K.
,
Linn
M.J.
,
Goldsmith
A.M.
,
Schumacher
R.E.
et al.
(
2010
)
Isolation of tracheal aspirate mesenchymal stromal cells predicts bronchopulmonary dysplasia
.
Pediatrics
126
,
e1127
e1133
[PubMed]
77.
Bonfield
T.L.
and
Caplan
A.I.
(
2010
)
Adult mesenchymal stem cells: an innovative therapeutic for lung diseases
.
Discov. Med.
9
,
337
345
[PubMed]
78.
Sutton
M.T.
and
Bonfield
T.L.
(
2014
)
Stem cells: innovations in clinical applications
.
Stem Cells Int.
2014
,
516278
[PubMed]
79.
Wang
G.S.
,
Bunnell
B.A.
,
Painter
R.G.
,
Quiniones
B.C.
,
Tom
S.
,
Lanson
N.A.
et al.
(
2005
)
Adult stem cells from bone marrow stroma differentiate into airway epithelial cells: Potential therapy for cystic fibrosis
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
186
191
[PubMed]
80.
Loi
R.
,
Beckett
T.
,
Goncz
K.K.
,
Suratt
B.T.
and
Weiss
D.J.
(
2006
)
Limited restoration of cystic fibrosis lung epithelium in vivo with adult bone marrow-derived cells
.
Am. J. Respir. Crit. Care Med.
173
,
171
179
[PubMed]
81.
Farrow
N.
,
Cmielewski
P.
,
Donnelley
M.
,
Rout-Pitt
N.
,
Moodley
Y.
,
Bertoncello
I.
et al.
(
2018
)
Epithelial disruption: a new paradigm enabling human airway stem cell transplantation
.
Stem Cell Res. Ther.
9
,
153
[PubMed]
82.
Conese
M.
,
Beccia
E.
,
Castellani
S.
,
Di Gioia
S.
,
Colombo
C.
,
Angiolillo
A.
et al.
(
2018
)
The long and winding road: stem cells for cystic fibrosis
.
Expert Opin. Biol. Ther.
18
,
281
292
[PubMed]
83.
Piro
D.
,
Rejman
J.
and
Conese
M.
(
2008
)
Stem cell therapy for cystic fibrosis: current status and future prospects
.
Expert Rev. Respir Med.
2
,
365
380
[PubMed]
84.
Sun
Z.
,
Li
F.
,
Zhou
X.
,
Chung
K.F.
,
Wang
W.
and
Wang
J.
(
2018
)
Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials
.
J. Thorac Dis.
10
,
1084
1098
[PubMed]
85.
Lee
M.
,
Jeong
S.Y.
,
Ha
J.
,
Kim
M.
,
Jin
H.J.
,
Kwon
S.J.
et al.
(
2014
)
Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo
.
Biochem. Biophys. Res. Commun.
446
,
983
989
[PubMed]
86.
Schu
S.
,
Nosov
M.
,
O’Flynn
L.
,
Shaw
G.
,
Treacy
O.
,
Barry
F.
et al.
(
2012
)
Immunogenicity of allogeneic mesenchymal stem cells
.
J. Cell. Mol. Med.
16
,
2094
2103
[PubMed]
87.
Huang
K.
,
Kang
X.W.
,
Wang
X.Y.
,
Wu
S.J.
,
Xiao
J.L.
,
Li
Z.G.
et al.
(
2015
)
Conversion of bone marrow mesenchymal stem cells into type II alveolar epithelial cells reduces pulmonary fibrosis by decreasing oxidative stress in rats
.
Mol. Med. Rep.
11
,
1685
1692
[PubMed]
88.
Cai
S.X.
,
Liu
A.R.
,
Chen
S.
,
He
H.L.
,
Chen
Q.H.
,
Xu
J.Y.
et al.
(
2015
)
Activation of Wnt/beta-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice
.
Stem Cell Res. Ther.
6
,
65
[PubMed]
89.
Gu
W.
,
Song
L.
,
Li
X.M.
,
Wang
D.
,
Guo
X.J.
and
Xu
W.G.
(
2015
)
Mesenchymal stem cells alleviate airway inflammation and emphysema in COPD through down-regulation of cyclooxygenase-2 via p38 and ERK MAPK pathways
.
Sci. Rep.
5
,
8733
90.
Hong
Y.
,
Kim
Y.S.
,
Hong
S.H.
and
Oh
Y.M.
(
2016
)
Therapeutic effects of adipose-derived stem cells pretreated with pioglitazone in an emphysema mouse model
.
Exp. Mol. Med.
48
,
e266
91.
Kim
Y.S.
,
Kim
J.Y.
,
Shin
D.M.
,
Huh
J.W.
,
Lee
S.W.
and
Oh
Y.M.
(
2014
)
Tracking intravenous adipose-derived mesenchymal stem cells in a model of elastase-induced emphysema
.
Tuberc Respir Dis.
77
,
116
123
[PubMed]
92.
Haddad
R.
and
Saldanha-Araujo
F.
(
2014
)
Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far?
Biomed. Res. Int.
2014
,
216806
93.
Tse
W.T.
,
Pendleton
J.D.
,
Beyer
W.M.
,
Egalka
M.C.
and
Guinan
E.C.
(
2003
)
Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation
.
Transplantation
75
,
389
397
[PubMed]
94.
Klyushnenkova
E.
,
Mosca
J.D.
,
Zernetkina
V.
,
Majumdar
M.K.
,
Beggs
K.J.
,
Simonetti
D.W.
et al.
(
2005
)
T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression
.
J. Biomed. Sci.
12
,
47
57
[PubMed]
95.
Najar
M.
,
Raicevic
G.
,
Fayyad-Kazan
H.
,
De Bruyn
C.
,
Bron
D.
,
Toungouz
M.
et al.
(
2012
)
Immune-related antigens, surface molecules and regulatory factors in human-derived mesenchymal stromal cells: the expression and impact of inflammatory priming
.
Stem Cell Rev.
8
,
1188
1198
[PubMed]
96.
Briones
J.
,
Novelli
S.
and
Sierra
J.
(
2011
)
T-cell costimulatory molecules in acute-graft-versus host disease: therapeutic implications
.
Bone Marrow Res.
2011
,
976793
[PubMed]
97.
Khattar
E.
,
Kumar
P.
,
Liu
C.Y.
,
Akincilar
S.C.
,
Raju
A.
,
Lakshmanan
M.
et al.
(
2016
)
Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression
.
J. Clin. Invest.
126
,
4045
4060
[PubMed]
98.
Akincilar
S.C.
,
Khattar
E.
,
Boon
P.L.
,
Unal
B.
,
Fullwood
M.J.
and
Tergaonkar
V.
(
2016
)
Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation
.
Cancer Discov
6
,
1276
1291
[PubMed]
99.
Di Nicola
M.
,
Carlo-Stella
C.
,
Magni
M.
,
Milanesi
M.
,
Longoni
P.D.
,
Matteucci
P.
et al.
(
2002
)
Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli
.
Blood
99
,
3838
43
[PubMed]
100.
Xu
G.
,
Zhang
Y.
,
Zhang
L.
,
Ren
G.
and
Shi
Y.
(
2007
)
The role of IL-6 in inhibition of lymphocyte apoptosis by mesenchymal stem cells
.
Biochem. Biophys. Res. Commun.
361
,
745
750
[PubMed]
101.
Benvenuto
F.
,
Ferrari
S.
,
Gerdoni
E.
,
Gualandi
F.
,
Frassoni
F.
,
Pistoia
V.
et al.
(
2007
)
Human mesenchymal stem cells promote survival of T cells in a quiescent state
.
Stem Cells
25
,
1753
1760
[PubMed]
102.
Groh
M.E.
,
Maitra
B.
,
Szekely
E.
and
Koc
O.N.
(
2005
)
Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells
.
Exp. Hematol.
33
,
928
934
[PubMed]
103.
Le Blanc
K.
,
Rasmusson
I.
,
Gotherstrom
C.
,
Seidel
C.
,
Sundberg
B.
,
Sundin
M.
et al.
(
2004
)
Mesenchymal stem cells inhibit the expression of CD25 (interleukin-2 receptor) and CD38 on phytohaemagglutinin-activated lymphocytes
.
Scand. J. Immunol.
60
,
307
315
[PubMed]
104.
Glennie
S.
,
Soeiro
I.
,
Dyson
P.J.
,
Lam
E.W.
and
Dazzi
F.
(
2005
)
Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells
.
Blood
105
,
2821
2827
[PubMed]
105.
Ramasamy
R.
,
Tong
C.K.
,
Seow
H.F.
,
Vidyadaran
S.
and
Dazzi
F.
(
2008
)
The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function
.
Cell. Immunol.
251
,
131
136
[PubMed]
106.
Su
J.
,
Chen
X.
,
Huang
Y.
,
Li
W.
,
Li
J.
,
Cao
K.
et al.
(
2014
)
Phylogenetic distinction of iNOS and IDO function in mesenchymal stem cell-mediated immunosuppression in mammalian species
.
Cell Death Differ.
21
,
388
396
[PubMed]
107.
Ren
G.
,
Su
J.
,
Zhang
L.
,
Zhao
X.
,
Ling
W.
,
L’Huillie
A.
et al.
(
2009
)
Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression
.
Stem Cells
27
,
1954
1962
[PubMed]
108.
Ren
G.
,
Zhang
L.
,
Zhao
X.
,
Xu
G.
,
Zhang
Y.
,
Roberts
A.I.
et al.
(
2008
)
Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide
.
Cell Stem Cell
2
,
141
150
[PubMed]
109.
Kovach
T.K.
,
Dighe
A.S.
,
Lobo
P.I.
and
Cui
Q.
(
2015
)
Interactions between MSCs and immune cells: implications for bone healing
.
J. Immunol. Res.
2015
,
752510
[PubMed]
110.
Luz-Crawford
P.
,
Kurte
M.
,
Bravo-Alegria
J.
,
Contreras
R.
,
Nova-Lamperti
E.
,
Tejedor
G.
et al.
(
2013
)
Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells
.
Stem Cell Res. Ther.
4
,
65
[PubMed]
111.
Duffy
M.M.
,
Ritter
T.
,
Ceredig
R.
and
Griffin
M.D.
(
2011
)
Mesenchymal stem cell effects on T-cell effector pathways
.
Stem Cell Res. Ther.
2
,
34
[PubMed]
112.
Sioud
M.
,
Mobergslien
A.
,
Boudabous
A.
and
Floisand
Y.
(
2011
)
Mesenchymal stem cell-mediated T cell suppression occurs through secreted galectins
.
Int. J. Oncol.
38
,
385
390
[PubMed]
113.
Lepelletier
Y.
,
Lecourt
S.
,
Renand
A.
,
Arnulf
B.
,
Vanneaux
V.
,
Fermand
J.P.
et al.
(
2010
)
Galectin-1 and semaphorin-3A are two soluble factors conferring T-cell immunosuppression to bone marrow mesenchymal stem cell
.
Stem Cells Dev.
19
,
1075
1079
[PubMed]
114.
Gieseke
F.
,
Kruchen
A.
,
Tzaribachev
N.
,
Bentzien
F.
,
Dominici
M.
and
Muller
I.
(
2013
)
Proinflammatory stimuli induce galectin-9 in human mesenchymal stromal cells to suppress T-cell proliferation
.
Eur. J. Immunol.
43
,
2741
2749
[PubMed]
115.
Augello
A.
,
Tasso
R.
,
Negrini
S.M.
,
Amateis
A.
,
Indiveri
F.
,
Cancedda
R.
et al.
(
2005
)
Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway
.
Eur. J. Immunol.
35
,
1482
1490
[PubMed]
116.
Djouad
F.
,
Plence
P.
,
Bony
C.
,
Tropel
P.
,
Apparailly
F.
,
Sany
J.
et al.
(
2003
)
Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals
.
Blood
102
,
3837
3844
[PubMed]
117.
Sato
K.
,
Ozaki
K.
,
Oh
I.
,
Meguro
A.
,
Hatanaka
K.
,
Nagai
T.
et al.
(
2007
)
Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells
.
Blood
109
,
228
234
[PubMed]
118.
Aggarwal
S.
and
Pittenger
M.F.
(
2005
)
Human mesenchymal stem cells modulate allogeneic immune cell responses
.
Blood
105
,
1815
1822
[PubMed]
119.
Meisel
R.
,
Zibert
A.
,
Laryea
M.
,
Gobel
U.
,
Daubener
W.
and
Dilloo
D.
(
2004
)
Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation
.
Blood
103
,
4619
4621
[PubMed]
120.
Najar
M.
,
Rouas
R.
,
Raicevic
G.
,
Boufker
H.I.
,
Lewalle
P.
,
Meuleman
N.
et al.
(
2009
)
Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6
.
Cytotherapy
11
,
570
583
[PubMed]
121.
Yang
S.H.
,
Park
M.J.
,
Yoon
I.H.
,
Kim
S.Y.
,
Hong
S.H.
,
Shin
J.Y.
et al.
(
2009
)
Soluble mediators from mesenchymal stem cells suppress T cell proliferation by inducing IL-10
.
Exp. Mol. Med.
41
,
315
324
[PubMed]
122.
Ghosh
A.S.
and
Tergaonkar
V.
(
2010
)
Telomeres and Inflammation: Rap1 Joins the Ends?
,
Taylor & Francis
123.
Teo
H.
,
Ghosh
S.
,
Luesch
H.
,
Ghosh
A.
,
Wong
E.T.
,
Malik
N.
et al.
(
2010
)
Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression
.
Nat. Cell Biol.
12
,
758
[PubMed]
124.
Zhang
Y.
,
Zhang
Z.
,
Gao
F.
,
Tse
H.F.
,
Tergaonkar
V.
and
Lian
Q.
(
2015
)
Paracrine regulation in mesenchymal stem cells: the role of Rap1
.
Cell Death Disease
6
,
e1932
125.
Qiu
B.
,
Han
W.
and
Tergaonkar
V.
(
2015
)
NUCKS: a potential biomarker in cancer and metabolic disease
.
Clin. Sci.
128
,
715
721
[PubMed]
126.
Qiu
B.
,
Shi
X.
,
Wong Ee
T.
,
Lim
J.
,
Bezzi
M.
,
Low
D.
et al.
(
2014
)
NUCKS Is a Positive Transcriptional Regulator of Insulin Signaling
.
Cell Rep.
7
,
1876
1886
[PubMed]
127.
Pomerantz
J.L.
and
Baltimore
D.
(
1999
)
NF‐κB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK‐related kinase
.
EMBO J.
18
,
6694
6704
[PubMed]
128.
Zhang
Y.
,
Chiu
S.
,
Liang
X.
,
Chai
Y.-H.
,
Qin
Y.
,
Wang
J.
et al.
(
2017
)
Absence of NUCKS augments paracrine effects of mesenchymal stem cells-mediated cardiac protection
.
Exp. Cell Res.
356
,
74
84
[PubMed]
129.
Cuerquis
J.
,
Romieu-Mourez
R.
,
Francois
M.
,
Routy
J.P.
,
Young
Y.K.
,
Zhao
J.
et al.
(
2014
)
Human mesenchymal stromal cells transiently increase cytokine production by activated T cells before suppressing T-cell proliferation: effect of interferon-gamma and tumor necrosis factor-alpha stimulation
.
Cytotherapy
16
,
191
202
[PubMed]
130.
Tang
G.N.
,
Li
C.L.
,
Yao
Y.
,
Xu
Z.B.
,
Deng
M.X.
,
Wang
S.Y.
et al.
(
2016
)
MicroRNAs involved in asthma after mesenchymal stem cells treatment
.
Stem Cells Dev.
25
,
883
896
[PubMed]
131.
Wang
S.Y.
,
Fan
X.L.
,
Yu
Q.N.
,
Deng
M.X.
,
Sun
Y.Q.
,
Gao
W.X.
et al.
(
2017
)
The lncRNAs involved in mouse airway allergic inflammation following induced pluripotent stem cell-mesenchymal stem cell treatment
.
Stem Cell Res. Ther.
8
,
2
[PubMed]
132.
Bustos
M.L.
,
Huleihel
L.
,
Meyer
E.M.
,
Donnenberg
A.D.
,
Donnenberg
V.S.
,
Sciurba
J.D.
et al.
(
2013
)
Activation of human mesenchymal stem cells impacts their therapeutic abilities in lung injury by increasing interleukin (IL)-10 and IL-1RN levels
.
Stem Cells Transl. Med.
2
,
884
895
[PubMed]
133.
Silva
L.H.A.
,
Antunes
M.A.
,
Dos Santos
C.C.
,
Weiss
D.J.
,
Cruz
F.F.
and
Rocco
P.R.M.
(
2018
)
Strategies to improve the therapeutic effects of mesenchymal stromal cells in respiratory diseases
.
Stem Cell Res. Ther.
9
,
45
[PubMed]
134.
Zhang
Y.
,
Chiu
S.
,
Liang
X.
,
Gao
F.
,
Zhang
Z.
,
Liao
S.
et al.
(
2015
)
Rap1-mediated nuclear factor-kappaB (NF-κB) activity regulates the paracrine capacity of mesenchymal stem cells in heart repair following infarction
.
Cell Death Discovery
1
,
15007
[PubMed]
135.
Pistoia
V.
and
Raffaghello
L.
(
2014
)
Unveiling the role of TNF-alpha in mesenchymal stromal cell-mediated immunosuppression
.
Eur. J. Immunol.
44
,
352
356
[PubMed]
136.
Dorronsoro
A.
,
Ferrin
I.
,
Salcedo
J.M.
,
Jakobsson
E.
,
Fernandez-Rueda
J.
,
Lang
V.
et al.
(
2014
)
Human mesenchymal stromal cells modulate T-cell responses through TNF-alpha-mediated activation of NF-kappaB
.
Eur. J. Immunol.
44
,
480
488
[PubMed]
137.
Tong
L.
and
Tergaonkar
V.
(
2014
)
Rho protein GTPases and their interactions with NFkappaB: crossroads of inflammation and matrix biology
.
Biosci. Rep.
34
,
e00115
138.
Liu
Y.
,
Tergaonkar
V.
,
Krishna
S.
and
Androphy
E.J.
(
1999
)
Human papillomavirus type 16 E6-enhanced susceptibility of L929 cells to tumor necrosis factor alpha correlates with increased accumulation of reactive oxygen species
.
J. Biol. Chem.
274
,
24819
24827
[PubMed]
139.
Xue
Q.
,
Luan
X.Y.
,
Gu
Y.Z.
,
Wu
H.Y.
,
Zhang
G.B.
,
Yu
G.H.
et al.
(
2010
)
The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity
.
Stem Cells Dev.
19
,
27
38
[PubMed]
140.
Saldanha-Araujo
F.
,
Haddad
R.
,
Farias
K.C.
,
Souza Ade
P.
,
Palma
P.V.
,
Araujo
A.G.
et al.
(
2012
)
Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-kappaB signalling
.
J. Cell. Mol. Med.
16
,
1232
1244
[PubMed]
141.
Francois
M.
,
Romieu-Mourez
R.
,
Li
M.
and
Galipeau
J.
(
2012
)
Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation
.
Mol. Ther.
20
,
187
195
[PubMed]
142.
Gao
S.
,
Mao
F.
,
Zhang
B.
,
Zhang
L.
,
Zhang
X.
,
Wang
M.
et al.
(
2014
)
Mouse bone marrow-derived mesenchymal stem cells induce macrophage M2 polarization through the nuclear factor-kappaB and signal transducer and activator of transcription 3 pathways
.
Exp. Biol. Med.
239
,
366
375
[PubMed]
143.
Cho
D.I.
,
Kim
M.R.
,
Jeong
H.Y.
,
Jeong
H.C.
,
Jeong
M.H.
,
Yoon
S.H.
et al.
(
2014
)
Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages
.
Exp. Mol. Med.
46
,
e70
[PubMed]
144.
Ciccocioppo
R.
,
Bernardo
M.E.
,
Sgarella
A.
,
Maccario
R.
,
Avanzini
M.A.
,
Ubezio
C.
et al.
(
2011
)
Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease
.
Gut
60
,
788
798
[PubMed]
145.
Paliwal
S.
,
Chaudhuri
R.
,
Agrawal
A.
and
Mohanty
S.
(
2018
)
Regenerative abilities of mesenchymal stem cells through mitochondrial transfer
.
J. Biomed. Sci.
25
[PubMed]
146.
Mahrouf-Yorgov
M.
,
Augeul
L.
,
Da Silva
C.C.
,
Jourdan
M.
,
Rigolet
M.
,
Manin
S.
et al.
(
2017
)
Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties
.
Cell Death Differ.
24
,
1224
1238
[PubMed]
147.
Ahmad
T.
,
Mukherjee
S.
,
Pattnaik
B.
,
Kumar
M.
,
Singh
S.
,
Kumar
M.
et al.
(
2014
)
Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy
.
EMBO J.
33
,
994
1010
[PubMed]
148.
Zhang
Y.
,
Yu
Z.
,
Jiang
D.
,
Liang
X.
,
Liao
S.
,
Zhang
Z.
et al.
(
2016
)
iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-alpha yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy
.
Stem Cell Rep.
7
,
749
763
[PubMed]
149.
Shen
J.
,
Zhang
J.H.
,
Xiao
H.
,
Wu
J.M.
,
He
K.M.
,
Lv
Z.Z.
et al.
(
2018
)
Mitochondria are transported along microtubules in membrane nanotubes to rescue distressed cardiomyocytes from apoptosis
.
Cell Death Dis.
9
,
81
[PubMed]
150.
Squillaro
T.
,
Peluso
G.
and
Galderisi
U.
(
2016
)
Clinical trials with mesenchymal stem cells: an update
.
Cell Transplant.
25
,
829
848
[PubMed]
151.
Trounson
A.
and
McDonald
C.
(
2015
)
Stem cell therapies in clinical trials: progress and challenges
.
Cell Stem Cell
17
,
11
22
[PubMed]
152.
Cruz
F.F.
and
Rocco
P.R.M.
(
2017
)
Stem-cell extracellular vesicles and lung repair
.
Stem Cell Investig.
4
,
78
[PubMed]
153.
Cruz
F.F.
,
Borg
Z.D.
,
Goodwin
M.
,
Sokocevic
D.
,
Wagner
D.E.
,
Coffey
A.
et al.
(
2015
)
Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice
.
Stem Cells Transl. Med.
4
,
1302
1316
[PubMed]
154.
de Castro
L.L.
,
Xisto
D.G.
,
Kitoko
J.Z.
,
Cruz
F.F.
,
Olsen
P.C.
,
Redondo
P.A.G.
et al.
(
2017
)
Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma
.
Stem Cell Res. Ther.
8
,
151
[PubMed]
155.
Abreu
S.C.
,
Weiss
D.J.
and
Rocco
P.R.
(
2016
)
Extracellular vesicles derived from mesenchymal stromal cells: a therapeutic option in respiratory diseases?
Stem Cell Res. Ther.
7
,
53
[PubMed]
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