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Mesenchymal Stromal/Stem Cells and Lung Transplantation: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Vitale Miceli.

Lung transplantation (LTx) has become the gold standard treatment for end-stage respiratory failure. Recently, extended lung donor criteria have been applied to decrease the mortality rate of patients on the waiting list. Moreover, ex vivo lung perfusion (EVLP) has been used to improve the number/quality of previously unacceptable lungs. Despite the above-mentioned progress, the morbidity/mortality of LTx remains high compared to other solid organ transplants. Lungs are particularly susceptible to ischemia-reperfusion injury, which can lead to graft dysfunction. Therefore, the success of LTx is related to the quality/function of the graft, and EVLP represents an opportunity to protect/regenerate the lungs before transplantation. Increasing evidence supports the use of mesenchymal stromal/stem cells (MSCs) as a therapeutic strategy to improve EVLP. The therapeutic properties of MSC are partially mediated by secreted factors. Hence, the strategy of lung perfusion with MSCs and/or their products pave the way for a new innovative approach that further increases the potential for the use of EVLP. 

  • lung transplantation
  • ex vivo lung perfusion
  • mesenchymal stromal/stem cells
  • lung preservation

1. Introduction

Lung transplantation (LTx) has become the treatment of choice for patients with end-stage respiratory failure and, over the past decades, the worldwide survival of lung transplant patients has increased significantly [1]. Unfortunately, the short- and long-term outcomes of LTxs are still less favorable than other solid organ transplants, the main faults being organ shortage and the fact that more than 80% of potential organ donors are not suitable or used for transplantation [2,3,4,5,6][2][3][4][5][6]. Moreover, other factors, such as postoperative graft dysfunction (PGD), infections, and rejection may also contribute to post-transplant mortality [7,8][7][8].
Although the use of extended-criteria lung donors and donors after cardio-circulatory death is increasing, there is still wide consensus in the transplant community that a large proportion of potentially viable grafts is discarded due to fear of early graft dysfunction and the increased postoperative morbidity and mortality of the recipient [1,3,9,10][1][3][9][10]. Ischemia-reperfusion injury (IRI) is the leading cause of early postoperative lung dysfunction, and is characterized by alveolar damage and lung edema usually occurring within 72 hours after LTx [11]. These pathological processes are driven by both oxidative stress and inflammatory pathways, which cause significant damage to the lung parenchyma, leading to the development of early PGD and consequent chronic lung allograft dysfunction [1,10,11,12][1][10][11][12]. Therefore, a reduction in these adverse effects could significantly improve the success of LTx.
Recently, it has been shown that the use of normothermic ex vivo lung perfusion (EVLP) may be helpful in increasing the number and improving the results of lung transplantation [13,14][13][14]. This procedure provides the opportunity to evaluate donor lung function, and different treatments can also be used to further reduce IRI [15,16,17][15][16][17]. Therefore, the improvement of this technique represents a promising strategy to increase the number of suitable organs and to advance LTx.
A suitable approach to improving EVLP technique consists of using mesenchymal stromal/stem cells (MSCs) and/or their secretome, which contains extracellular vesicles (EVs, such as exosomes and EXOs) and other bioactive molecules, including cytokines, chemokines, growth factors, angiogenic and immunomodulatory factors [18,19,20,21][18][19][20][21]. Although the mechanisms are not fully defined yet, it has been widely demonstrated in both preclinical and clinical studies that therapeutic effects of MSCs are mediated, at least in part, by paracrine factors [21,22,23,24][21][22][23][24]. MSCs’ therapeutic properties have been also evaluated in a phase II clinical trial to treat acute respiratory distress syndrome (ARDS) [25]. MSCs and/or their products are able to mitigate both lung injury and inflammation in different experimental models, and the infusion of MSCs protects transplanted lungs from IRI [26,27,28,29][26][27][28][29]. Moreover, it has been found that MSC-based treatment during EVLP is associated with a decrease in ischemic injury of human donor lungs [30,31,32][30][31][32]. In this case, to avoid the founding of infused MSCs in the lung parenchyma, cell-free therapies, including the use of MSC-derived EXOs and MSC-derived conditioned medium (CM), could be considered new approaches to obtaining MSCs’ beneficial effects. EXOs are nanosized structures carrying functional molecules [33], and can be considered a promising therapeutic tool for acute lung injury because they reduce inflammation and enhance tissue regeneration [34,35,36][34][35][36]. Similarly, MSC-derived CM has demonstrated beneficial effects on lung diseases [37,38,39,40,41,42,43][37][38][39][40][41][42][43]. The use of MSC-derived products rather than direct use of MSCs can prevent all the risks associated with live-cell transplants. Therefore, the use of these products is emerging as a promising approach in the field of LTx.

2. Mesenchymal Stromal/Stem Cell (MSC)-based Therapeutic Approaches to Improve Lung Transplantation

Survival rates after LTx have improved, yet outcomes are still poorer than other solid organ transplants [3,6][3][6]. The advances of the lung preservation techniques and the better understanding of the main mechanisms governing IRI processes can lead to a significant reduction in the incidence of lung PGD [118][44]. This condition is a type of acute lung injury that results from IRI and represents the major cause of early post-transplant morbidity and mortality [119][45]. In recent years, it has been shown that MSCs are able to reduce PGD. Jarvinen et al. showed that human lung resident MSCs have the potential to modulate immunological responses [120][46], and McAuley et al. revealed that MSCs can have the ability to restore alveolar fluid clearance in human lungs rejected after transplantation [32]. Moreover, allogenic MSCs were able to reduce both acute lung injury (ALI) in an animal model and CLAD in human lung transplant recipients [121,122][47][48]. In fact, much scientific evidence has revealed the therapeutic properties of MSCs in different lung disease models [123[49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64],124,125,126,127,128,129,130,131,132,133,134,135,136,137,138], including those induced by IRI-related pathological processes. Table 1 summarized both in vitro and in vivo studies reporting the use of MSCs and/or their products in preventing lung injury/dysfunction. For LTx, there is a clinical need to implement new strategies for the prevention and treatment of IRI, and MSCs and/or their products represent a new therapeutic tool to prevent the occurrence of unwanted complications to further improve the success of LTx.
Table 1. Summary of studies reporting the use of MSCs and/or their products in preventing lung injury.
Use of Cells or Their Products Study Model Effects Due to MSC Treatment Mechanisms References
BM-MSCs Mouse lung IRI Protection against cold IRI in lung transplants Improved arterial blood oxygenation capacity, reduced levels of pro-inflammatory cytokine and cell apoptosis [29]
MSC-derived EVs Rat lung IRI and EVLP Improved tissue integrity and metabolism Decrease in vascular resistance and rise in perfusate NO metabolites; Up-regulation of genes involved in the resolution of both inflammation and oxidative stress [34]
UC-MSCs and UC-MSC-derived EVs Mouse lung IRI Attenuation of lung dysfunction and injury by improving the efficacy of EVLP Decreased levels of edema, neutrophil infiltration and myeloperoxidase; decrease in pro-inflammatory cytokines and increase in KGF, PGE2 and IL-10; [35]
UC-MSC-derived EVs E. coli-induced rat lung injury Increased survival Enhanced phagocytosis of E. coli [36]
BM-MSCs and BM-MSC-derived CM Rat lung Injury Attenuation of lung injury Reduced levels of pro-inflammatory cytokine [37]
BM-MSCs and BM-MSC-derived CM Ventilator-induced rat lung injury Reduction in injury and improvement in recovery Reduced levels of edema, neutrophil, and alveolar IL-6 concentrations [38]
BM-MSC-derived CM Rat lung IRI Protection against lung IRI Decrease in both pro-inflammatory cytokines and infiltrating inflammatory cells, and increase in both M2-like macrophages and regulatory T cells [39]
AdMSC-derived CM LPS-induced mouse lung injury Reduction in ARDS indices Reduced endothelial barrier hyperpermeability and activation of pro-inflammatory and pro-apoptotic pathways in endothelium. [40]
AMSC-derived CM In vitro model of human lung IRI Attenuation of IRI effects by improving the efficacy of in vitro EVLP Increase in anti-inflammatory factors and up-regulation of anti-apoptotic factors [41]
BM-MSCs and AdMSC-derived CM Rat and human alveolar epithelial cell injury Decreased cell injury Decrease in pro-inflammatory factors and increase in anti-inflammatory factors; inhibition of p38 MAPK and translocation of Bcl-2 to the nucleus; Increased expression of cytoprotective glucose-regulated proteins [43]
MSCs Swine lung IRI Attenuation of ischemic injury in donor lungs during EVLP and attenuation of IRI after transplantation Increased levels of HGF and IL-4 and decreased levels of TNFα and cell death markers [65]
BM-MSCs HCL- and LPS-induced rat lung injury Decreased inflammation Decrease in proinflammatory cytokines,

neutrophil infiltration, hemorrhage and interstitial

edema		 [122][48]
UC-MSCs and UC-MSC-derived EVs Rat neonatal hyperoxic lung injuries Attenuation of hyperoxic lung injuries Increased alveolarization and angiogenesis; decrease in

alveolar epithelial cell death, macrophages and cytokines in lung		 [123][49]
BM-MSC-derived EVs Mouse pulmonary arterial hypertension Reduction in pulmonary vascular remodeling and right ventricle hypertrophy Increased levels of anti-inflammatory and anti-proliferative miRs including miRs-34a,-122,-124, and -127. [124][50]
BM-MSCs Rat lung IRI Attenuation of lung pathologic injury Reduced myeloperoxidase production, decreased levels of of pro-inflammatory cytokine and cell apoptosis in lung tissue [125][51]
BM-MSCs E. coli-induced rat pneumonia Reduction in lung injury; improvement in survival; reduction in lung bacterial load and suppression of inflammation Enhanced macrophage phagocytic capacity and increase in lung and systemic concentrations of the antimicrobial peptide LL37 [126][52]
BM-MSCs Hyperoxia-induced rat lung injury Mitigation of emphysema Increased number of alveoli and decrease in α-SMA expression by myofibroblasts [127][53]
BM-MSCs and BM-MSC-derived CM Cigarette-smoke-induced rat emphysema Alleviation of emphysema and increase in the number of small pulmonary vessels Decrease in pulmonary artery medial wall thickness and reduction in apoptosis in lungs with emphysema [128][54]
BM-MSCs and BM-MSC-derived CM LPS-induced mouse lung injury Resolution of lung injury by attenuating lung inflammation Decrease in neutrophils and increase in M2 in BAL [129][55]
BM-MSCs and BM-MSC-derived CM Mouse chronic obstructive pulmonary disease Reduction in injury Reduced levels of inflammation, fibrosis and apoptotic and increased production of HGF [130][56]
AdMSC-derived EVs Elastase-induced mouse emphysema Reduction in lung emphysema Increased levels of FGF2 [131][57]
BM-MSCs Bleomycin-induced rat pulmonary fibrosis Decreased fibrosis Attenuation of NRF2, NQO1, HO-1, γ-GCS, lipid peroxidation, and increase in SOD activity [132][58]
UC-MSCs Rat lung IRI Reduction in Oxidative stress damage and inflammation Reduced levels of MPO activity and neutrophil markers; reduction in reactive oxygen species production [133][59]
AdMSCs and AdMSC-derived CM Sulfur mustard-induced mouse lung injury Reduction in progressive histopathologic changes in the lung Reducd levels of both M1 and M2 cells, TNF-α and IL-1β [134][60]
BM-MSC-derived CM Bleomycin-induced rat pulmonary fibrosis Protection against lung fibrosis Decrease in lung inflammation, fibrotic scores, collagen deposition, and cell apoptosis [135][61]
SHEDs and SHED-derived CM Bleomycin-induced mouse pulmonary fibrosis Attenuation of lung injury and improvement in survival rate Reduced levels of pro-inflammatory factors and increased levels of anti-inflammatory factors and M2 cells [136][62]
BM-MSCs Swine lung transplantation Improvement in dynamic lung compliance Reduced intrapulmonary edema [137][63]
BM-MSC-derived EVs E. Coli-induced mouse lung Injury Reduction in lung edema and inflammation Decrease in lung protein permeability, neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid; increase in KGF in BAL [138][64]
AdMSCs Rat lung IRI Attenuation of lung damage after IRI Suppression of oxidative stress and inflammatory reaction [139][66]
UC-MSCs Swine lung IRI Attenuation of IRI by improving the efficacy of EVLP Increased levels of VEGF and decreased concentration of circulating IL-8 [140][67]
BM-MSCs Human lung IRI and EVLP Decreased cold ischemic injury Decrease in pro-inflammatory cytokines and increase in anti-inflammatory cytokines [30]
BM-MSCs and BM-MSC-derived CM E. coli-induced human lung injury Increase in alveolar fluid clearance in lungs during EVLP KGF secretion [31]
BM-MSCs Human lungs rejected for transplantation and subjected to prolonged ischemic time Restoration of alveolar fluid clearance KGF secretion [32]
BM-MSC-derived EVs Human lungs rejected for transplantation Increase in alveolar fluid clearance in donor lungs during EVLP Improved airway and hemodynamic parameters [141][68]
AdMSCs Clinical trial Attenuation of IRI and host immunological reaction towards the graft Not determined NCT04714801
BM-MSCs Clinical trial Attenuation of graft rejection and bronchiolitis obliteran syndrome (BOS) Not determined NCT02181712
MSCs: mesenchymal stromal/stem cells; BM-MSCs: bone-marrow-derived MSCs; AMSCs: amnion-derived MSCs; UC-MSCs: umbilical-cord-derived MSCs; AdMSCs: adipose-derived MSCs; SHEDs: stromal/stem cells from human exfoliated deciduous teeth; IRI: ischemia-reperfusion injury; EVLP: ex vivo lung perfusion; CM: conditioned medium; EVs: extracellular vesicles; BAL: bronchoalveolar lavage; ARDS: acute respiratory distress syndrome.

2.1. Therapeutic Effects of MSCs on Ischemia-Reperfusion Injury (IRI)

Ischemia-reperfusion injury events can occur in the case of stroke or myocardial infarction, as well as in solid organ transplantation. Prolonged ischemia causes deprivation of both oxygen and nutrients, leading to cellular metabolic and ultrastructural pathological changes [142][69]. Pathological effects mediated by IRI are often potentiated by the onset of inflammation processes, affecting organ quality and transplant outcomes in solid organ transplantation [143][70]. In this case, IRI-associated injury can be attenuated by cold ischemia storage, but it cannot be completely prevented [144][71]. Moreover, oxidative stress is a crucial process of IRI-associated effects, leading to the production of toxic molecules [142][69]. Much scientific evidence shows that MSCs have been able to decrease inflammation and IRI in both in vitro and in vivo models, and these effects are mediated by different mechanisms, including paracrine activity producing a functional secretome [145][72]. It has been shown that AdMSCs were able to reduce myocardial IRI and to decrease pro-inflammatory cytokine in an in vivo mouse model [146][73]. In an IRI rat model, Cui et al. demonstrated that AdMSC-derived EXOs were able to protect the myocardium [147][74].

2.2. MSCs as Therapeutic Tool to Improve EVLP

Focusing on expanding the donor pool to reduce the mortality of lung transplant in recipient patients, different approaches are currently being explored, including the extended criteria for the selection of donors [153][75], and lung procurement from donors after cardiac death [3]. These strategies have led to the use of the so-called “marginal” organs that do not fulfill the standard criteria of donor lungs. For this scenario, the ex vivo lung perfusion (EVLP) technique was developed in order to: 1. assess graft function after procurement and before implantation; 2. preserve the graft after harvesting; and 3. repair/regenerate potential grafts previously considered unsuitable for transplantation [17,154][17][76]. In a lung-transplanted rat model, EVLP treatment was able to protect lung tissue against IRI side effects [155][77] and, to further reduce IRI complications, pharmacological treatments are possible either by intravascular or endobronchial administration [15,16][15][16]. Moreover, although the molecular mechanisms underpinning lung regeneration during EVLP have not been explored yet, recent studies have analyzed metabolic/proteomic events to reveal potential regenerative effects of EVLP [156,157][78][79]. This may offer an additional opportunity to evaluate both questionable donor lungs and the effectiveness of new treatments.
The overall data show that the role of MSCs in improving lung recovery appears to be mediated mainly by MSC paracrine signaling; furthermore, the use of MSCs and/or their products, including EVs and CM, represents a promising approach to improving EVLP reconditioning of transplanted lungs. Because of MSCs ability to secrete paracrine factors with anti-inflammatory, anti-oxidant and anti-apoptotic properties, MSCs and/or their products represent a useful tool for integration with EVLP to further preserve/regenerate lung tissue by attenuating IRI during LTx (Figure 1).
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Figure 1. Therapeutic strategies to improve ex vivo lung perfusion (EVLP) during lung transplantation. EVLP treatment may sometimes be not sufficient to mitigate ischemia-reperfusion injury (IRI) effects, and lung graft can reveal the lung to have a poor quality after transplantation. The treatment with mesenchymal stromal/stem cells (MSCs) and/or their products (conditioned medium and/or exosomes containing growth factors, cytokines and chemokines) can effectively potentiate EVLP performance and attenuate IRI adverse events by inducing: 1. tissue repair/regeneration; 2. inhibition of reactive oxygen species (ROS); 3. immunomodulation. These effects can lead to the improvement of clinical outcomes after lung transplantation.

3. Conclusions and Perspectives

Many preclinical studies in animal models have clearly shown that the therapeutic effects of MSCs on lung injury, and specifically on ischemia-reperfusion injury after LTx, are mediated by the reduction in inflammation [26,27,28,29,34,35,36,37,39,40,65,125,129,137,140][26][27][28][29][34][35][36][37][39][40][65][51][55][63][67]. Moreover, in a preclinical setting, it has also been demonstrated that MSCs have been able to protect human lungs during transplantation [30,31,32,141][30][31][32][68]. Interestingly, these effects appear to be related, at least in part, to the paracrine secretion of MSC factors, including proteins and EVs (such as EXOs), which offer an opportunity to develop new cell-free treatments for human lung diseases. On the other hand, only two clinical studies (clinicaltrial.gov, NCT number: NCT04714801 and NCT02181712) are currently testing the potential role of MSC therapy in lung transplantation to avoid graft rejection.
Therefore, although many works have shown the potential application of MSCs in improving the outcomes of lung transplantation, these effects have not been confirmed in appropriate clinical studies yet. Several issues can explain the limited use of MSCs in this field. There are still relevant limitations to the use of MSC therapy in lung transplant clinical practice. MSCs display mutable properties related to the biological and technical variability of their preparation, and these may impact on the therapeutic potency of MSCs [21,88,95][21][80][81]. In particular, the optimal source, dose, and priming of MSCs is crucial and should be optimized. The best EVLP strategy and protocols to treat lungs before transplantation still need to be elucidated. In addition, another important aspect to be clarified is whether the use of MSC-derived products, such as secretome and/or EXOs, can offer additional benefits compared to standard preparations. The understanding of these critical issues could allow the introduction of MSC treatments in clinical lung transplantation. More efficacy studies—for example, in large animals—are needed to determine the best approach for a human clinical setting. Further investigation is needed to better integrate MSC therapy with EVLP use. This new strategy can lead to enhanced EVLP performance, with the ultimate goal of increasing the number of donor lungs and their quality. Moreover, the routine use of EVLP in clinical practice can favor an improvement in lung transplant management and outcomes.

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