Efficacy and safety of mesenchymal stem cell therapy for acute respiratory distress syndrome—a systematic review and
meta-analysis
Lingyan Fang, Fangyuan Hu, Han Li, Wei Chang, Ling Liu
Abstract
Background: Mesenchymal stem cells (MSC) therapy for acute respiratory distress syndrome (ARDS) represents a burgeoning treatment approach, supported by numerous preclinical studies confirming its efficacy. Our study aims to provide a comprehensive evaluation of both the safety and effectiveness of MSC.
Methods: We conducted searches across three databases (PubMed, Embase, Cochrane) for randomized controlled studies up to June 23, 2024. A meta-analysis was performed on variables including adverse events, mortality, changes in the PaO2/FiO2 ratio, intensive care unit (ICU), length of stay, ventilation-free days, and changes in pro-inflammatory and anti-inflammatory cytokines. Relative risk (RR) values were employed for dichotomous variables, while mean difference (MD) and standard mean difference (SMD) were used for continuous variables. Risk bias was assessed using risk of bias 2 (ROB2).
Results: The meta-analysis encompassed 17 experiments involving 796 patients, with 410 undergoing MSC treatment and 386 in the control group. Primary outcomes indicated that MSC treatment did not escalate adverse events [RR =1.04; 95% confidence interval (CI): 0.90, 1.19; P=0.59; I2=0%]. On the contrary, it significantly diminishes the mortality (RR =0.79; 95% CI: 0.64, 0.97; P=0.02; I2=0%). Regarding secondary outcomes, MSCs led to a significant improvement in the PaO2/FiO2 ratio for ARDS patients (SMD =0.53; 95% CI: 0.15, 0.92; P=0.007; I2=0%). However, there were no significant differences in ICU length of stay (MD =−1.77; 95% CI: −6.97, 3.43; P=0.50; I2=63%) and ventilation-free days (MD =−1.29; 95% CI: −4.09, 1.51; P=0.37; I2=0%). MSCs significantly lowered C-reactive protein (CRP) (SMD =−0.65; 95% CI: −1.18, −0.13; P=0.01; I2=56%) and interleukin-6 (IL-6) levels compared to the control group (SMD =−0.76; 95% CI: −1.34, −0.17; P=0.01; I2=74%). However, changes in interleukin-10 (AIL-10) (SMD =−0.46; 95% CI: −1.51, 0.58; P=0.38; I2=77%), and changes in tumor necrosis factor-alpha (ATNF-α) (SMD =−1.5; 95% CI: −3.39, 0.40; P=0.12; I2=92%) levels showed no significant changes.
Conclusions: MSC therapy demonstrates reliable safety, with a significant impact on reducing mortality and improving certain clinical symptoms. Moreover, in certain aspects, it may alleviate the inflammatory response in ARDS. Nonetheless, these findings necessitate validation through additional high-quality randomized controlled trials.
Keywords: Acute respiratory distress syndrome (ARDS); mesenchymal stem cells (MSCs); mortality; adverse events; meta-analysis
article original link: click here
References
References
- Matthay MA, Zemans RL, Zimmerman GA, et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 2019;5:18.
- ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-33.
- Sweeney RM, McAuley DF. Acute respiratory distress syndrome. Lancet 2016;388:2416-30.
- Huppert LA, Matthay MA, Ware LB. Pathogenesis of Acute Respiratory Distress Syndrome. Semin Respir Crit Care Med 2019;40:31-9.
- Bellani G, Laffey JG, Pham T, 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.
- Gorman EA, O’Kane CM, McAuley DF. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management. Lancet 2022;400:1157-70.
- Gorman E, Millar J, McAuley D, et al. Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential. Expert Rev Respir Med 2021;15:301-24.
- Gupta N, Krasnodembskaya A, Kapetanaki M, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012;67:533-9.
- Németh K, Leelahavanichkul A, Yuen PS, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 2009;15:42-9.
- Devaney J, Horie S, Masterson C, et al. Human mesenchymal stromal cells decrease the severity of acute lung injury induced by E. coli in the rat. Thorax 2015;70:625-35.
- Yang Y, Hu S, Xu X, et al. The Vascular Endothelial Growth Factors-Expressing Character of Mesenchymal Stem Cells Plays a Positive Role in Treatment of Acute Lung Injury In Vivo. Mediators Inflamm 2016;2016:2347938.
- Krasnodembskaya A, Samarani G, Song Y, et al. Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. Am J Physiol Lung Cell Mol Physiol 2012;302:L1003-13.
- Adas G, Cukurova Z, Yasar KK, et al. The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial. Cell Transplant 2021;30:9636897211024942.
- Aghayan HR, Salimian F, Abedini A, et al. Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): safety profile assessment. Stem Cell Res Ther 2022;13:365.
- Bowdish ME, Barkauskas CE, Overbey JR, et al. A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19. Am J Respir Crit Care Med 2023;207:261-70.
- Dilogo IH, Aditianingsih D, Sugiarto A, et al. Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial. Stem Cells Transl Med 2021;10:1279-87.
- Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, et al.
Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: clinical trial phase I & II. Stem Cell Res Ther 2022;13:96.
- Gorman EA, Rynne J, Gardiner HJ, et al. Repair of Acute Respiratory Distress Syndrome in COVID-19 by Stromal Cells (REALIST-COVID Trial): A Multicenter, Randomized, Controlled Clinical Trial. Am J Respir Crit Care Med 2023;208:256-69.
- Kaffash Farkhad N, Sedaghat A, Reihani H, et al. Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: a successful phase 1, control-placebo group, clinical trial. Stem Cell Res Ther 2022;13:283.
- Lanzoni G, Linetsky E, Correa D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med 2021;10:660-73.
- Martínez-Muñoz ME, Payares-Herrera C, Lipperheide I, et al. Mesenchymal stromal cell therapy for COVID-19 acute respiratory distress syndrome: a double-blind randomised controlled trial. Bone Marrow Transplant 2024;59:777-84.
- Matthay MA, Calfee CS, Zhuo H, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med 2019;7:154-62.
- Monsel A, Hauw-Berlemont C, Mebarki M, et al. Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: a multicenter randomized double-blind trial. Crit Care 2022;26:48.
- Pochon C, Laroye C, Kimmoun A, et al. Efficacy of Wharton Jelly Mesenchymal Stromal Cells infusions in moderate to severe SARS-Cov-2 related acute respiratory distress syndrome: a phase 2a double-blind randomized controlled trial. Front Med (Lausanne) 2023;10:1224865.
- Rebelatto CLK, Senegaglia AC, Franck CL, et al. Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: a randomized clinical trial. Stem Cell Res Ther 2022;13:122.
- Shi L, Huang H, Lu X, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther 2021;6:58.
- Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther 2020;11:361.
- Zarrabi M, Shahrbaf MA, Nouri M, et al. Allogenic mesenchymal stromal cells and their extracellular vesicles in COVID-19 induced ARDS: a randomized controlled trial. Stem Cell Res Ther 2023;14:169.
- Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res 2014;15:39.
- Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
- Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015;3:24-32.
- Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal Stem Cell Therapy for COVID-19: Present or Future. Stem Cell Rev Rep 2020;16:427-33.
- Sengupta V, Sengupta S, Lazo A, et al. Exosomes Derived from Bone Marrow Mesenchymal Stem Cells as Treatment for Severe COVID-19. Stem Cells Dev 2020;29:747-54.
- McIntyre LA, Moher D, Fergusson DA, et al. Efficacy of Mesenchymal Stromal Cell Therapy for Acute Lung Injury in Preclinical Animal Models: A Systematic Review. PLoS One 2016;11:e0147170.
- Chen MC, Lai KS, Chien KL, et al. pcMSC Modulates Immune Dysregulation in Patients With COVID-19-Induced Refractory Acute Lung Injury. Front Immunol 2022;13:871828.
- Zhou Y, Yamamoto Y, Xiao Z, et al. The Immunomodulatory Functions of Mesenchymal Stromal/Stem Cells Mediated via Paracrine Activity. J Clin Med 2019;8:1025.
- Atluri S, Manchikanti L, Hirsch JA. Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. Pain Physician 2020;23:E71-83.
- Hayes M, Masterson C, Devaney J, et al. Therapeutic efficacy of human mesenchymal stromal cells in the repair of established ventilator-induced lung injury in the rat. Anesthesiology 2015;122:363-73.
- Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. Stem Cells 2016;34:2210-23.
- Pedrazza L, Cunha AA, Luft C, et al. Mesenchymal stem cells improves survival in LPS-induced acute lung injury
acting through inhibition of NETs formation. J Cell Physiol 2017;232:3552-64.
- Perlee D, de Vos AF, Scicluna BP, et al. Human Adipose-Derived Mesenchymal Stem Cells Modify Lung Immunity and Improve Antibacterial Defense in Pneumosepsis Caused by Klebsiella pneumoniae. Stem Cells Transl Med 2019;8:785-96.
- Rocheteau P, Chatre L, Briand D, et al. Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy. Nat Commun 2015;6:10145.
- Zhu H, Xiong Y, Xia Y, et al. Therapeutic Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Acute Lung Injury Mice. Sci Rep 2017;7:39889.
- Shimizu M. Clinical Features of Cytokine Storm Syndrome. In: Cron R, Behrens E. editors. Cytokine Storm Syndrome. Cham Springer 2019:31-41.
- Meduri GU, Headley S, Kohler G, et al. Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest 1995;107:1062-73.
- Bárcia RN, Santos JM, Filipe M, et al. What Makes Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells Superior Immunomodulators When Compared to Bone Marrow Derived Mesenchymal Stromal Cells? Stem Cells Int 2015;2015:583984.
- Cóndor JM, Rodrigues CE, Sousa Moreira Rd, et al. Treatment With Human Wharton’s Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction. Stem Cells Transl Med 2016;5:1048-57.
- Li X, Bai J, Ji X, et al. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med 2014;34:695-704.
