Cellular therapies in ARDS
1Department of Respiratory Physiopathology, Parc Taulí Research and Innovation Institution Foundation (I3PT), 08208 Sabadell, Spain
2Autonomous University of Barcelona, 08193 Bellaterra, Spain
3Biomedical Research Network Centre of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain
4Department of Intensive Care Medicine, Parc Taulí Health Corporation, 08208 Sabadell, Spain
5Anaesthesia and Intensive Care Medicine, School of Medicine, Clinical Sciences Institute, National University of Ireland, H91 TK33 Galway, Ireland
6Department of Anaesthesia, SAOLTA University Health Group, Galway University Hospitals, H91 TK33Galway, Ireland
7Institute of Biomedical Research of Barcelona, Spanish National Research Council (IIBB-CSIC), 08036 Barcelona, Spain
DOI: 10.22514/sv.2022.059 Vol.18,Issue 5,September 2022 pp.68-74
Submitted: 04 April 2022 Accepted: 09 June 2022
Published: 08 September 2022
*Corresponding Author(s): Aina Areny-Balagueró E-mail: email@example.com
Acute respiratory distress syndrome (ARDS) is a critical illness characterized by a severe hypoxemic respiratory failure, caused by an inflammatory response which results in diffuse lung damage. Despite decades of research, the treatment of ARDS remains supportive. However, in recent years, cell-based therapies have been the subject of intensive ongoing research efforts, showing relevant therapeutic potential in preclinical ARDS models. Among all the different cells that have been identified as suitable candidates for use, mesenchymal stromal cells (MSCs) have been the most attractive candidates and have generated significant interest. MSCs are multipotent adult stem/stromal cells that can modulate the immune response and enhance repair of damaged tissue in multiple in vivo models. Their promising effect seems to be not primarily mediated by MSCs differentiation and engraftment but more by the paracrine release of different soluble mediators and cellular components such as extracellular vesicles (EVs). Preclinical experiments have provided encouraging evidence for the therapeutic potential of MSCs, leading to the launch of several phase I and II clinical trials that have shown safety of MSCs in ARDS, which became very common nowadays due to the Coronavirus disease (COVID-19) pandemic. However, some translational challenges have yet to be solved, such as the reproducibility of cell harvest, storage, reconstitution, and administration of cells/cell-products, before the therapeutic potential of stem cells therapies can be realized.
ARDS; Cell therapy; MSCs; EVs
Aina Areny-Balagueró,Antonio Artigas,John G Laffey,Daniel Closa. Cellular therapies in ARDS. Signa Vitae. 2022. 18(5);68-74.
 Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. The Lancet. 1967; 2: 319–323.
 ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012; 307: 2526–2533.
 Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nature Reviews Disease Primers. 2019; 5: 18.
 COVID-ICU Group on behalf of the REVA Network and the COVID-ICU Investigators. Clinical characteristics and day-90 outcomes of 4244 critically ill adults with COVID-19: a prospective cohort study. Intensive Care Medicine. 2021; 47: 60–73.
 Daviet F, Guilloux P, Hraiech S, Tonon D, Velly L, Bourenne J, et al. Impact of obesity on survival in COVID-19 ARDS patients receiving ECMO: results from an ambispective observational cohort. Annals of Intensive Care. 2021; 11: 157.
 Cortegiani A, Madotto F, Gregoretti C, Bellani G, Laffey JG, Pham T, et al. Immunocompromised patients with acute respiratory distress syndrome: secondary analysis of the LUNG SAFE database. Critical Care. 2018; 22: 157.
 Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in Intensive Care units in 50 countries. JAMA. 2016; 315: 788–800.
 Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. The New England Journal of Medicine. 2015; 372: 2185–2196.
 Lee J, Corl K, Levy MM. Fluid therapy and acute respiratory distress syndrome. Critical Care Clinics. 2021; 37: 867–875.
 Dulhunty JM, Roberts JA, Davis JS, Webb SAR, Bellomo R, Gomersall C, et al. A multicenter randomized trial of continuous versus intermittent β-lactam infusion in severe sepsis. American Journal of Respiratory and Critical Care Medicine. 2015; 192: 1298–1305.
 Kumar N, Kumar A, Kumar A, Pattanayak A, Singh K, Singh P. NUTRIC score as a predictor of outcome in COVID-19 ARDS patients: a retrospective observational study. Indian Journal of Anaesthesia. 2021; 65: 669.
 Brave H, MacLoughlin R. State of the art review of cell therapy in the treatment of lung disease, and the potential for aerosol delivery. International Journal of Molecular Sciences. 2020; 21: 6435.
 Guillamat-Prats R, Camprubí-Rimblas M, Bringué J, Tantinyà N, Artigas A. Cell therapy for the treatment of sepsis and acute respiratory distress syndrome. Annals of Translational Medicine. 2017; 5: 446.
 Silva JD, Krasnodembskaya AD. Investigation of the MSC paracrine effects on alveolar—capillary barrier integrity in the in vitro models of ARDS. Methods in Molecular Biology. 2021; 97: 63–81.
 Abraham A, Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Translational Medicine. 2020; 9: 28–38.
 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Experimental Hematology. 1976; 4: 267–274
 Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. The Lancet Respiratory Medicine. 2015; 3: 24–32.
 Byrnes D, Masterson CH, Artigas A, Laffey JG. Mesenchymal stem/stromal cells therapy for sepsis and acute respiratory distress syndrome. Seminars in Respiratory and Critical Care Medicine. 2021; 42: 020–039.
 Wu J, Song D, Li Z, Guo B, Xiao Y, Liu W, et al. Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis. Cell Research. 2020; 30: 794–809.
 Kotton DN, Fabian AJ, Mulligan RC. Failure of bone marrow to reconstitute lung epithelium. American Journal of Respiratory Cell and Molecular Biology. 2005; 33: 328–334.
 Hu C, Li L. Preconditioning influences mesenchymal stem cell properties in vitro and in vivo. Journal of Cellular and Molecular Medicine. 2018; 22: 1428–1442.
 Budinger GRS, Mutlu GM, Urich D, Soberanes S, Buccellato LJ, Hawkins K, et al. Epithelial cell death is an important contributor to oxidant-mediated acute lung injury. American Journal of Respiratory and Critical Care Medicine. 2011; 183: 1043–1054.
 Short KR, Kasper J, van der Aa S, Andeweg AC, Zaaraoui-Boutahar F, Goeijenbier M, et al. Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions. European Respiratory Journal. 2016; 47: 954–966.
 Fang X, Neyrinck AP, Matthay MA, Lee JW. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. Journal of Biological Chemistry. 2010; 285: 26211–26222.
 Curley GF, Hayes M, Ansari B, Shaw G, Ryan A, Barry F, et al. Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat. Thorax. 2012; 67: 496–501.
 Maron-Gutierrez T, Silva JD, Asensi KD, Bakker-Abreu I, Shan Y, Diaz BL, et al. Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice. Critical Care Medicine. 2013; 41: e319–e333.
 Cai SX, Liu AR, Chen S, He HL, Chen QH, Xu JY, et al. Activation of Wnt/β-catenin signalling promotes mesenchymal stem cells to repair injured alveolar epithelium induced by lipopolysaccharide in mice. Stem Cell Research & Therapy. 2015; 6: 65.
 Xiao K, He W, Guan W, Hou F, Yan P, Xu J, et al. Mesenchymal stem cells reverse EMT process through blocking the activation of NF-κB and Hedgehog pathways in LPS-induced acute lung injury. Cell Death & Disease. 2020; 11: 863.
 Tian J, Cui X, Sun J, Zhang J. Exosomal microRNA-16-5p from adipose mesenchymal stem cells promotes TLR4-mediated M2 macrophage polarization in septic lung injury. International Immunopharmacology. 2021; 98: 107835.
 Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine. 2001; 163: 1376–1383.
 Hao Q, Zhu YG, Monsel A, Gennai S, Lee T, Xu F, et al. Study of bone marrow and embryonic stem cell-derived human mesenchymal stem cells for treatment of escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells Translational Medicine. 2015; 4: 832–840.
 Ihara K, Fukuda S, Enkhtaivan B, Trujillo R, Perez-Bello D, Nelson C, et al. Adipose-derived stem cells attenuate pulmonary microvascular hy-perpermeability after smoke inhalation. PLoS One. 2017; 12: e0185937.
 Goolaerts A, Pellan-Randrianarison N, Larghero J, Vanneaux V, Uzunhan Y, Gille T, et al. Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2014; 306: L975–L985.
 Zhou Z, Hua Y, Ding Y, Hou Y, Yu T, Cui Y, et al. Conditioned medium of bone marrow mesenchymal stem cells involved in acute lung injury by regulating epithelial sodium channels via miR-34c. Frontiers in Bioengineering and Biotechnology. 2021; 9: 640116.
 Ho MSH, Mei SHJ, Stewart DJ. The Immunomodulatory and therapeutic effects of mesenchymal stromal cells for acute lung injury and sepsis. Journal of Cellular Physiology. 2015; 230: 2606–2617.
 Yao M, Cui B, Zhang W, Ma W, Zhao G, Xing L. Exosomal miR-21 secreted by IL-1β-primed-mesenchymal stem cells induces macrophage M2 polarization and ameliorates sepsis. Life Sciences. 2021; 264: 118658.
 Kwon M, Ghanta S, Ng J, Tsoyi K, Lederer JA, Bronson RT, et al. Expression of stromal cell–derived factor-1 by mesenchymal stromal cells impacts neutrophil function during sepsis. Critical Care Medicine. 2020; 48: e409–e417.
 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105: 1815–1822.
 Ribeiro A, Laranjeira P, Mendes S, Velada I, Leite C, Andrade P, et al. Mesenchymal stem cells from umbilical cord matrix, adipose tissue and bone marrow exhibit different capability to suppress peripheral blood B, natural killer and T cells. Stem Cell Research & Therapy. 2013; 4: 125.
 Németh K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E2—dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine. 2009; 15: 42–49.
 dos Santos CC, Murthy S, Hu P, Shan Y, Haitsma JJ, Mei SHJ, et al. Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. The American Journal of Pathology. 2012; 181: 1681–1692.
 Abreu SC, Rolandsson Enes S, Dearborn J, Goodwin M, Coffey A, Borg ZD, et al. Lung inflammatory environments differentially alter mesenchymal stromal cell behavior. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2019; 317: L823–L831.
 Rolandsson Enes S, Hampton TH, Barua J, McKenna DH, Dos Santos CC, Amiel E, et al. Healthy versus inflamed lung environments dif-ferentially affect mesenchymal stromal cells. The European Respiratory Journal. 2021; 58: 2004149.
 Bartlett RS, Guille JT, Chen X, Christensen MB, Wang SF, Thibeault SL. Mesenchymal stromal cell injection promotes vocal fold scar repair without long-term engraftment. Cytotherapy. 2016; 18: 1284–1296.
 Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 2001; 105: 369–377.
 Hezam K, Mo R, Wang C, Liu Y, Li Z. Anti-inflammatory effects of mesenchymal stem cells and their secretomes in pneumonia. Current Pharmaceutical Biotechnology. 2022; 23: 1153–1167.
 Shologu N, Scully M, Laffey JG, O’Toole D. Human mesenchymal stem cell secretome from bone marrow or adipose-derived tissue sources for treatment of hypoxia-induced pulmonary epithelial injury. International Journal of Molecular Sciences. 2018; 19: 2996.
 Porzionato A, Zaramella P, Dedja A, Guidolin D, Bonadies L, Macchi V, et al. Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2021; 320: L688–L704.
 Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, et al. Mesenchymal stromal cell exosomes ameliorate experimen-tal bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. American Journal of Respiratory and Critical Care Medicine. 2018; 197: 104–116.
 Moll G, Alm JJ, Davies LC, von Bahr L, Heldring N, Stenbeck-Funke L, et al. Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells. 2014; 32: 2430–2442.
 Luetzkendorf J, Nerger K, Hering J, Moegel A, Hoffmann K, Hoefers C, et al. Cryopreservation does not alter main characteristics of good manufacturing process—grade human multipotent mesenchymal stromal cells including immunomodulating potential and lack of malignant transformation. Cytotherapy. 2015; 17: 186–198.
 Pinky, Gupta S, Krishnakumar V, Sharma Y, Dinda AK, Mohanty
S. Mesenchymal stem cell derived exosomes: a nano platform for therapeutics and drug delivery in combating COVID-19. Stem Cell Reviews and Reports. 2021; 17: 33–43.
 Gimona M, Brizzi MF, Choo ABH, Dominici M, Davidson SM, Grillari J, et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy. 2021; 23: 373–380.
 Lu H, Cook T, Poirier C, Merfeld-Clauss S, Petrache I, March KL, et al. Pulmonary retention of adipose stromal cells following intravenous delivery is markedly altered in the presence of ARDS. Cell Transplantation. 2016; 25: 1635–1643.
 Kang SK, Shin IS, Ko MS, Jo JY, Ra JC. Journey of mesenchymal stem cells for homing: strategies to enhance efficacy and safety of stem cell therapy. Stem Cells International. 2012; 2012: 1–11.
 Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI. The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs. 2001; 169: 12–20.
 Lian J, Lin J, Zakaria N, Yahaya BH. Acute lung injury: disease modelling and the therapeutic potential of stem cells. Cell Biology and Translational Medicine. 2020; 306: 149–166.
 Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, et al. Allogeneic human mesenchymal stem cells in patients with idiopathic pulmonary fibrosis via intravenous delivery (AETHER) chest. 2017; 151: 971–981.
 Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. the Lancet Respiratory Medicine. 2015; 3: 24-32.
 Fernández-Francos S, Eiro N, González-Galiano N, Vizoso FJ. Mes-enchymal stem cell-based therapy as an alternative to the treatment of acute respiratory distress syndrome: current evidence and future perspectives. International Journal of Molecular Sciences. 2021; 22: 7850.
 Abdelgawad M, Bakry NS, Farghali AA, Abdel-Latif A, Lotfy A. Mesenchymal stem cell-based therapy and exosomes in COVID-19: current trends and prospects. Stem Cell Research & Therapy. 2021; 12: 469.
 Xu Z, Huang Y, Zhou J, Deng X, He W, Liu X, et al. Current status of cell-based therapies for COVID-19: evidence from mesenchymal stromal cells in sepsis and ARDS. Frontiers in Immunology. 2021; 12: 738697.
 Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells and Development. 2020; 29: 747–754.
 Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. The Lancet. Respiratory Medicine. 2019; 7: 154–162.
 Avanzini MA, Mura M, Percivalle E, Bastaroli F, Croce S, Valsecchi C, et al. Human mesenchymal stromal cells do not express ACE2 and TMPRSS2 and are not permissive to SARS-CoV-2 infection. Stem Cells Translational Medicine. 2021; 10: 636–642.
 Schäfer R, Spohn G, Bechtel M, Bojkova D, Baer PC, Kuçi S, et al. Human Mesenchymal Stromal Cells Are Resistant to SARS-CoV-2 Infection under Steady-State, Inflammatory Conditions and in the Presence of SARS-CoV-2-Infected Cells. Stem Cell Reports. 2021; 16: 419–427.
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