You're using an outdated browser. Please upgrade to a modern browser for the best experience.
Mesenchymal Stromal/Stem Cells and Lung Transplantation
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cells11050826

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]. Moreover, other factors, such as postoperative graft dysfunction (PGD), infections, and rejection may also contribute to post-transplant mortality [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]. 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]. 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]. This procedure provides the opportunity to evaluate donor lung function, and different treatments can also be used to further reduce IRI [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]. 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]. 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]. 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]. 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]. Similarly, MSC-derived CM has demonstrated beneficial effects on lung diseases [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]. 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 [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 [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 [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 [47][48]. In fact, much scientific evidence has revealed the therapeutic properties of MSCs in different lung disease models [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64], 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.
Table
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		 [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		 [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. [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 [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 [52]
BM-MSCs Hyperoxia-induced rat lung injury Mitigation of emphysema Increased number of alveoli and decrease in α-SMA expression by myofibroblasts [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 [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 [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 [56]
AdMSC-derived EVs Elastase-induced mouse emphysema Reduction in lung emphysema Increased levels of FGF2 [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 [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 [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 [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 [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 [62]
BM-MSCs Swine lung transplantation Improvement in dynamic lung compliance Reduced intrapulmonary edema [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 [64]
AdMSCs Rat lung IRI Attenuation of lung damage after IRI Suppression of oxidative stress and inflammatory reaction [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 [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 [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 [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 [70]. In this case, IRI-associated injury can be attenuated by cold ischemia storage, but it cannot be completely prevented [71]. Moreover, oxidative stress is a crucial process of IRI-associated effects, leading to the production of toxic molecules [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 [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 [73]. In an IRI rat model, Cui et al. demonstrated that AdMSC-derived EXOs were able to protect the myocardium [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 [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][76]. In a lung-transplanted rat model, EVLP treatment was able to protect lung tissue against IRI side effects [77] and, to further reduce IRI complications, pharmacological treatments are possible either by intravascular or endobronchial administration [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 [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).
Cells 11 00826 g001
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][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][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][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.

References

  1. van der Mark, S.C.; Hoek, R.A.S.; Hellemons, M.E. Developments in lung transplantation over the past decade. Eur. Respir Rev. 2020, 29, 190132.
  2. Forgie, K.A.; Fialka, N.; Freed, D.H.; Nagendran, J. Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review. Cells 2021, 10, 1417.
  3. Keshavamurthy, S.; Rodgers-Fischl, P. Donation after circulatory death (DCD)-lung procurement. Indian. J. Thorac. Cardiovasc. Surg. 2021, 37, 425–432.
  4. Opelz, G.; Dohler, B.; Ruhenstroth, A.; Cinca, S.; Unterrainer, C.; Stricker, L.; Scherer, S.; Gombos, P.; Susal, C.; Daniel, V.; et al. The collaborative transplant study registry. Transpl. Rev. (Orlando). 2013, 27, 43–45.
  5. Shepherd, H.M.; Gauthier, J.M.; Puri, V.; Kreisel, D.; Nava, R.G. Advanced considerations in organ donors. J. Thorac Dis. 2021, 13, 6528–6535.
  6. Thabut, G.; Mal, H. Outcomes after lung transplantation. J. Thorac Dis. 2017, 9, 2684–2691.
  7. Gagliotti, C.; Morsillo, F.; Moro, M.L.; Masiero, L.; Procaccio, F.; Vespasiano, F.; Pantosti, A.; Monaco, M.; Errico, G.; Ricci, A.; et al. Infections in liver and lung transplant recipients: A national prospective cohort. Eur. J. Clin. Microbiol. Infect. Dis. 2018, 37, 399–407.
  8. Sun, H.; Deng, M.; Chen, W.; Liu, M.; Dai, H.; Wang, C. Graft dysfunction and rejection of lung transplant, a review on diagnosis and management. Clin. Respir. J. 2022, 16, 5–12.
  9. Bozso, S.; Vasanthan, V.; Luc, J.G.; Kinaschuk, K.; Freed, D.; Nagendran, J. Lung transplantation from donors after circulatory death using portable ex vivo lung perfusion. Can. Respir. J. 2015, 22, 47–51.
  10. Laubach, V.E.; Sharma, A.K. Mechanisms of lung ischemia-reperfusion injury. Curr. Opin. Organ. Transplant. 2016, 21, 246–252.
  11. de Perrot, M.; Liu, M.; Waddell, T.K.; Keshavjee, S. Ischemia-reperfusion-induced lung injury. Am. J. Respir. Crit. Care Med. 2003, 167, 490–511.
  12. Kawashima, M.; Juvet, S.C. The role of innate immunity in the long-term outcome of lung transplantation. Ann. Transl. Med. 2020, 8, 412.
  13. Charles, E.J.; Huerter, M.E.; Wagner, C.E.; Sharma, A.K.; Zhao, Y.; Stoler, M.H.; Mehaffey, J.H.; Isbell, J.M.; Lau, C.L.; Tribble, C.G.; et al. Donation After Circulatory Death Lungs Transplantable Up to Six Hours After Ex Vivo Lung Perfusion. Ann. Thorac. Surg. 2016, 102, 1845–1853.
  14. Cypel, M.; Yeung, J.C.; Machuca, T.; Chen, M.; Singer, L.G.; Yasufuku, K.; de Perrot, M.; Pierre, A.; Waddell, T.K.; Keshavjee, S. Experience with the first 50 ex vivo lung perfusions in clinical transplantation. J. Thorac. Cardiovasc. Surg. 2012, 144, 1200–1206.
  15. Huerter, M.E.; Sharma, A.K.; Zhao, Y.; Charles, E.J.; Kron, I.L.; Laubach, V.E. Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism. Ann. Thorac. Surg. 2016, 102, 385–393.
  16. Martens, A.; Boada, M.; Vanaudenaerde, B.M.; Verleden, S.E.; Vos, R.; Verleden, G.M.; Verbeken, E.K.; Van Raemdonck, D.; Schols, D.; Claes, S.; et al. Steroids can reduce warm ischemic reperfusion injury in a porcine donation after circulatory death model with ex vivo lung perfusion evaluation. Transpl. Int. 2016, 29, 1237–1246.
  17. Nakajima, D.; Date, H. Ex vivo lung perfusion in lung transplantation. Gen. Thorac. Cardiovasc. Surg. 2021, 69, 625–630.
  18. Gallo, A.; Cuscino, N.; Contino, F.; Bulati, M.; Pampalone, M.; Amico, G.; Zito, G.; Carcione, C.; Centi, C.; Bertani, A.; et al. Changes in the Transcriptome Profiles of Human Amnion-Derived Mesenchymal Stromal/Stem Cells Induced by Three-Dimensional Culture: A Potential Priming Strategy to Improve Their Properties. Int. J. Mol. Sci. 2022, 23, 863.
  19. Konala, V.B.; Mamidi, M.K.; Bhonde, R.; Das, A.K.; Pochampally, R.; Pal, R. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration. Cytotherapy 2016, 18, 13–24.
  20. Lo Nigro, A.; Gallo, A.; Bulati, M.; Vitale, G.; Paini, D.S.; Pampalone, M.; Galvagno, D.; Conaldi, P.G.; Miceli, V. Amnion-Derived Mesenchymal Stromal/Stem Cell Paracrine Signals Potentiate Human Liver Organoid Differentiation: Translational Implications for Liver Regeneration. Front. Med. (Lausanne) 2021, 8, 746298.
  21. Miceli, V.; Bulati, M.; Iannolo, G.; Zito, G.; Gallo, A.; Conaldi, P.G. Therapeutic Properties of Mesenchymal Stromal/Stem Cells: The Need of Cell Priming for Cell-Free Therapies in Regenerative Medicine. Int. J. Mol. Sci. 2021, 22, 763.
  22. Jimenez-Puerta, G.J.; Marchal, J.A.; Lopez-Ruiz, E.; Galvez-Martin, P. Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use. J. Clin. Med. 2020, 9, 445.
  23. Madrigal, M.; Rao, K.S.; Riordan, N.H. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J. Transl. Med. 2014, 12, 260.
  24. Mohammadipoor, A.; Antebi, B.; Batchinsky, A.I.; Cancio, L.C. Therapeutic potential of products derived from mesenchymal stem/stromal cells in pulmonary disease. Respir. Res. 2018, 19, 218.
  25. Wick, K.D.; Leligdowicz, A.; Zhuo, H.; Ware, L.B.; Matthay, M.A. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight 2021, 6, e148983.
  26. Abreu, S.C.; Weiss, D.J.; Rocco, P.R. Extracellular vesicles derived from mesenchymal stromal cells: A therapeutic option in respiratory diseases? Stem Cell Res. Ther. 2016, 7, 53.
  27. Morrison, T.J.; Jackson, M.V.; Cunningham, E.K.; Kissenpfennig, A.; McAuley, D.F.; O’Kane, C.M.; Krasnodembskaya, A.D. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017, 196, 1275–1286.
  28. Schmelzer, E.; Miceli, V.; Chinnici, C.M.; Bertani, A.; Gerlach, J.C. Effects of Mesenchymal Stem Cell Coculture on Human Lung Small Airway Epithelial Cells. BioMed Res. Int. 2020, 2020, 9847579.
  29. Tian, W.; Liu, Y.; Zhang, B.; Dai, X.; Li, G.; Li, X.; Zhang, Z.; Du, C.; Wang, H. Infusion of mesenchymal stem cells protects lung transplants from cold ischemia-reperfusion injury in mice. Lung 2015, 193, 85–95.
  30. La Francesca, S.; Ting, A.E.; Sakamoto, J.; Rhudy, J.; Bonenfant, N.R.; Borg, Z.D.; Cruz, F.F.; Goodwin, M.; Lehman, N.A.; Taggart, J.M.; et al. Multipotent adult progenitor cells decrease cold ischemic injury in ex vivo perfused human lungs: An initial pilot and feasibility study. Transplant. Res. 2014, 3, 19.
  31. Lee, J.W.; Fang, X.; Gupta, N.; Serikov, V.; Matthay, M.A. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc. Natl. Acad. Sci. USA 2009, 106, 16357–16362.
  32. McAuley, D.F.; Curley, G.F.; Hamid, U.I.; Laffey, J.G.; Abbott, J.; McKenna, D.H.; Fang, X.; Matthay, M.A.; Lee, J.W. Clinical grade allogeneic human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am. J. Physiol. Lung Cell Mol. Physiol. 2014, 306, L809–L815.
  33. Ullah, M.; Kodam, S.P.; Mu, Q.; Akbar, A. Microbubbles versus Extracellular Vesicles as Therapeutic Cargo for Targeting Drug Delivery. ACS Nano 2021, 15, 3612–3620.
  34. Lonati, C.; Bassani, G.A.; Brambilla, D.; Leonardi, P.; Carlin, A.; Maggioni, M.; Zanella, A.; Dondossola, D.; Fonsato, V.; Grange, C.; et al. Mesenchymal stem cell-derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury. J. Heart Lung Transplant. 2019, 38, 1306–1316.
  35. Stone, M.L.; Zhao, Y.; Robert Smith, J.; Weiss, M.L.; Kron, I.L.; Laubach, V.E.; Sharma, A.K. Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death. Respir. Res. 2017, 18, 212.
  36. Varkouhi, A.K.; Jerkic, M.; Ormesher, L.; Gagnon, S.; Goyal, S.; Rabani, R.; Masterson, C.; Spring, C.; Chen, P.Z.; Gu, F.X.; et al. Extracellular Vesicles from Interferon-gamma-primed Human Umbilical Cord Mesenchymal Stromal Cells Reduce Escherichia coli-induced Acute Lung Injury in Rats. Anesthesiology 2019, 130, 778–790.
  37. Chailakhyan, R.K.; Aver’yanov, A.V.; Zabozlaev, F.G.; Sobolev, P.A.; Sorokina, A.V.; Akul’shin, D.A.; Gerasimov, Y.V. Comparison of the efficiency of transplantation of bone marrow multipotent mesenchymal stromal cells cultured under normoxic and hypoxic conditions and their conditioned media on the model of acute lung injury. Bull. Exp. Biol. Med. 2014, 157, 138–142.
  38. Hayes, M.; Curley, G.F.; Masterson, C.; Devaney, J.; O’Toole, D.; Laffey, J.G. Mesenchymal stromal cells are more effective than the MSC secretome in diminishing injury and enhancing recovery following ventilator-induced lung injury. Intensive Care Med. Exp. 2015, 3, 29.
  39. Hwang, B.; Liles, W.C.; Waworuntu, R.; Mulligan, M.S. Pretreatment with bone marrow-derived mesenchymal stromal cell-conditioned media confers pulmonary ischemic tolerance. J. Thorac. Cardiovasc. Surg. 2016, 151, 841–849.
  40. Lu, H.; Poirier, C.; Cook, T.; Traktuev, D.O.; Merfeld-Clauss, S.; Lease, B.; Petrache, I.; March, K.L.; Bogatcheva, N.V. Conditioned media from adipose stromal cells limit lipopolysaccharide-induced lung injury, endothelial hyperpermeability and apoptosis. J. Transl. Med. 2015, 13, 67.
  41. Miceli, V.; Bertani, A.; Chinnici, C.M.; Bulati, M.; Pampalone, M.; Amico, G.; Carcione, C.; Schmelzer, E.; Gerlach, J.C.; Conaldi, P.G. Conditioned Medium from Human Amnion-Derived Mesenchymal Stromal/Stem Cells Attenuating the Effects of Cold Ischemia-Reperfusion Injury in an In Vitro Model Using Human Alveolar Epithelial Cells. Int. J. Mol. Sci. 2021, 22, 510.
  42. Moreira, A.; Naqvi, R.; Hall, K.; Emukah, C.; Martinez, J.; Moreira, A.; Dittmar, E.; Zoretic, S.; Evans, M.; Moses, D.; et al. Effects of mesenchymal stromal cell-conditioned media on measures of lung structure and function: A systematic review and meta-analysis of preclinical studies. Stem Cell Res. Ther. 2020, 11, 399.
  43. Shologu, N.; Scully, M.; Laffey, J.G.; O’Toole, D. Human Mesenchymal Stem Cell Secretome from Bone Marrow or Adipose-Derived Tissue Sources for Treatment of Hypoxia-Induced Pulmonary Epithelial Injury. Int. J. Mol. Sci. 2018, 19, 2996.
  44. Wilkey, B.J.; Abrams, B.A. Mitigation of Primary Graft Dysfunction in Lung Transplantation: Current Understanding and Hopes for the Future. Semin. Cardiothorac. Vasc. Anesth. 2020, 24, 54–66.
  45. Christie, J.D.; Kotloff, R.M.; Ahya, V.N.; Tino, G.; Pochettino, A.; Gaughan, C.; DeMissie, E.; Kimmel, S.E. The effect of primary graft dysfunction on survival after lung transplantation. Am. J. Respir. Crit. Care Med. 2005, 171, 1312–1316.
  46. Jarvinen, L.; Badri, L.; Wettlaufer, S.; Ohtsuka, T.; Standiford, T.J.; Toews, G.B.; Pinsky, D.J.; Peters-Golden, M.; Lama, V.N. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J. Immunol. 2008, 181, 4389–4396.
  47. Chambers, D.C.; Enever, D.; Lawrence, S.; Sturm, M.J.; Herrmann, R.; Yerkovich, S.; Musk, M.; Hopkins, P.M. Mesenchymal Stromal Cell Therapy for Chronic Lung Allograft Dysfunction: Results of a First-in-Man Study. Stem Cells Transl. Med. 2017, 6, 1152–1157.
  48. Guillamat-Prats, R.; Camprubi-Rimblas, M.; Puig, F.; Herrero, R.; Tantinya, N.; Serrano-Mollar, A.; Artigas, A. Alveolar Type II Cells or Mesenchymal Stem Cells: Comparison of Two Different Cell Therapies for the Treatment of Acute Lung Injury in Rats. Cells 2020, 9, 1816.
  49. Ahn, S.Y.; Park, W.S.; Kim, Y.E.; Sung, D.K.; Sung, S.I.; Ahn, J.Y.; Chang, Y.S. Vascular endothelial growth factor mediates the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicles against neonatal hyperoxic lung injury. Exp. Mol. Med. 2018, 50, 1–12.
  50. Aliotta, J.M.; Pereira, M.; Wen, S.; Dooner, M.S.; Del Tatto, M.; Papa, E.; Goldberg, L.R.; Baird, G.L.; Ventetuolo, C.E.; Quesenberry, P.J.; et al. Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc. Res. 2016, 110, 319–330.
  51. Chen, S.; Chen, L.; Wu, X.; Lin, J.; Fang, J.; Chen, X.; Wei, S.; Xu, J.; Gao, Q.; Kang, M. Ischemia postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion-induced lung injury in rats. J. Surg. Res. 2012, 178, 81–91.
  52. Devaney, J.; Horie, S.; Masterson, C.; Elliman, S.; Barry, F.; O’Brien, T.; Curley, G.F.; O’Toole, D.; Laffey, J.G. Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat. Thorax 2015, 70, 625–635.
  53. Gulasi, S.; Atici, A.; Yilmaz, S.N.; Polat, A.; Yilmaz, M.; Lacin, M.T.; Orekici, G.; Celik, Y. Mesenchymal stem cell treatment in hyperoxia-induced lung injury in newborn rats. Pediatrics Int. Off. J. Jpn. Pediatric Soc. 2016, 58, 206–213.
  54. Huh, J.W.; Kim, S.Y.; Lee, J.H.; Lee, J.S.; Van Ta, Q.; Kim, M.; Oh, Y.M.; Lee, Y.S.; Lee, S.D. Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am. J. Physiol. Lung Cell Mol. Physiol. 2011, 301, L255–L266.
  55. Ionescu, L.; Byrne, R.N.; van Haaften, T.; Vadivel, A.; Alphonse, R.S.; Rey-Parra, G.J.; Weissmann, G.; Hall, A.; Eaton, F.; Thebaud, B. Stem cell conditioned medium improves acute lung injury in mice: In vivo evidence for stem cell paracrine action. Am. J. Physiol. Lung Cell Mol. Physiol. 2012, 303, L967–L977.
  56. Kennelly, H.; Mahon, B.P.; English, K. Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD. Sci. Rep. 2016, 6, 38207.
  57. Kim, Y.S.; Kim, J.Y.; Cho, R.; Shin, D.M.; Lee, S.W.; Oh, Y.M. Adipose stem cell-derived nanovesicles inhibit emphysema primarily via an FGF2-dependent pathway. Exp. Mol. Med. 2017, 49, e284.
  58. Ni, S.; Wang, D.; Qiu, X.; Pang, L.; Song, Z.; Guo, K. Bone marrow mesenchymal stem cells protect against bleomycin-induced pulmonary fibrosis in rat by activating Nrf2 signaling. Int. J. Clin. Exp. Pathol. 2015, 8, 7752–7761.
  59. Pacienza, N.; Santa-Cruz, D.; Malvicini, R.; Robledo, O.; Lemus-Larralde, G.; Bertolotti, A.; Marcos, M.; Yannarelli, G. Mesenchymal Stem Cell Therapy Facilitates Donor Lung Preservation by Reducing Oxidative Damage during Ischemia. Stem Cells Int. 2019, 2019, 8089215.
  60. Sadeghi, S.; Mosaffa, N.; Hashemi, S.M.; Mehdi Naghizadeh, M.; Ghazanfari, T. The immunomodulatory effects of mesenchymal stem cells on long term pulmonary complications in an animal model exposed to a sulfur mustard analog. Int. Immunopharmacol. 2020, 80, 105879.
  61. Shen, Q.; Chen, B.; Xiao, Z.; Zhao, L.; Xu, X.; Wan, X.; Jin, M.; Dai, J.; Dai, H. Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis. Mol. Med. Rep. 2015, 11, 2831–2837.
  62. Wakayama, H.; Hashimoto, N.; Matsushita, Y.; Matsubara, K.; Yamamoto, N.; Hasegawa, Y.; Ueda, M.; Yamamoto, A. Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice. Cytotherapy 2015, 17, 1119–1129.
  63. Wittwer, T.; Rahmanian, P.; Choi, Y.H.; Zeriouh, M.; Karavidic, S.; Neef, K.; Christmann, A.; Piatkowski, T.; Schnapper, A.; Ochs, M.; et al. Mesenchymal stem cell pretreatment of non-heart-beating-donors in experimental lung transplantation. J. Cardiothorac. Surg. 2014, 9, 151.
  64. Zhu, Y.G.; Feng, X.M.; Abbott, J.; Fang, X.H.; Hao, Q.; Monsel, A.; Qu, J.M.; Matthay, M.A.; Lee, J.W. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 2014, 32, 116–125.
  65. Nakajima, D.; Watanabe, Y.; Ohsumi, A.; Pipkin, M.; Chen, M.; Mordant, P.; Kanou, T.; Saito, T.; Lam, R.; Coutinho, R.; et al. Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation. J. Heart Lung Transplant. 2019, 38, 1214–1223.
  66. Sun, C.K.; Yen, C.H.; Lin, Y.C.; Tsai, T.H.; Chang, L.T.; Kao, Y.H.; Chua, S.; Fu, M.; Ko, S.F.; Leu, S.; et al. Autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model. J. Transl. Med. 2011, 9, 118.
  67. Mordant, P.; Nakajima, D.; Kalaf, R.; Iskender, I.; Maahs, L.; Behrens, P.; Coutinho, R.; Iyer, R.K.; Davies, J.E.; Cypel, M.; et al. Mesenchymal stem cell treatment is associated with decreased perfusate concentration of interleukin-8 during ex vivo perfusion of donor lungs after 18-hour preservation. J. Heart Lung Transplant. 2016, 35, 1245–1254.
  68. Gennai, S.; Monsel, A.; Hao, Q.; Park, J.; Matthay, M.A.; Lee, J.W. Microvesicles Derived From Human Mesenchymal Stem Cells Restore Alveolar Fluid Clearance in Human Lungs Rejected for Transplantation. Am. J. Transplant. 2015, 15, 2404–2412.
  69. Wu, M.Y.; Yiang, G.T.; Liao, W.T.; Tsai, A.P.; Cheng, Y.L.; Cheng, P.W.; Li, C.Y.; Li, C.J. Current Mechanistic Concepts in Ischemia and Reperfusion Injury. Cell. Physiol. Biochem. 2018, 46, 1650–1667.
  70. Slegtenhorst, B.R.; Dor, F.J.; Rodriguez, H.; Voskuil, F.J.; Tullius, S.G. Ischemia/reperfusion Injury and its Consequences on Immunity and Inflammation. Curr. Transplant. Rep. 2014, 1, 147–154.
  71. Ponticelli, C.E. The impact of cold ischemia time on renal transplant outcome. Kidney Int. 2015, 87, 272–275.
  72. Oliva, J. Therapeutic Properties of Mesenchymal Stem Cell on Organ Ischemia-Reperfusion Injury. Int. J. Mol. Sci. 2019, 20, 5511.
  73. Takamura, M.; Usui, S.; Inoue, O.; Ootsuji, H.; Takashima, S.I.; Nomura, A.; Kato, T.; Murai, H.; Furusho, H.; Sakai, Y.; et al. Adipose-derived regenerative cells exert beneficial effects on systemic responses following myocardial ischemia/reperfusion. Cardiol. J. 2016, 23, 685–693.
  74. Cui, X.; He, Z.; Liang, Z.; Chen, Z.; Wang, H.; Zhang, J. Exosomes From Adipose-derived Mesenchymal Stem Cells Protect the Myocardium Against Ischemia/Reperfusion Injury Through Wnt/beta-Catenin Signaling Pathway. J. Cardiovasc. Pharmacol. 2017, 70, 225–231.
  75. Neizer, H.; Singh, G.B.; Gupta, S.; Singh, S.K. Addressing donor-organ shortages using extended criteria in lung transplantation. Ann. Cardiothorac. Surg. 2020, 9, 49–50.
  76. Rosso, L.; Zanella, A.; Righi, I.; Barilani, M.; Lazzari, L.; Scotti, E.; Gori, F.; Mendogni, P. Lung transplantation, ex-vivo reconditioning and regeneration: State of the art and perspectives. J. Thorac Dis. 2018, 10, S2423–S2430.
  77. Lonati, C.; Bassani, G.A.; Brambilla, D.; Leonardi, P.; Carlin, A.; Faversani, A.; Gatti, S.; Valenza, F. Influence of ex vivo perfusion on the biomolecular profile of rat lungs. FASEB J. 2018, 32, 5532–5549.
  78. Roffia, V.; De Palma, A.; Lonati, C.; Di Silvestre, D.; Rossi, R.; Mantero, M.; Gatti, S.; Dondossola, D.; Valenza, F.; Mauri, P.; et al. Proteome Investigation of Rat Lungs subjected to Ex Vivo Perfusion (EVLP). Molecules 2018, 23, 3061.
  79. Shin, J.; Hsin, M.K.; Baciu, C.; Chen, Y.; Zamel, R.; Machuca, T.; Yeung, J.; Cypel, M.; Keshavjee, S.; Liu, M. Use of metabolomics to identify strategies to improve and prolong ex vivo lung perfusion for lung transplants. J. Heart Lung Transplant. 2021, 40, 525–535.
  80. Galipeau, J.; Sensebe, L. Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell 2018, 22, 824–833.
  81. Ullah, I.; Subbarao, R.B.; Rho, G.J. Human mesenchymal stem cells - current trends and future prospective. Biosci. Rep. 2015, 35, e00191.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Transplantation
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Vitale Miceli
View Times: 471
Revisions: 2 times (View History)
Update Date: 14 Mar 2022
Table of Contents
Academic Video Service
Feedback