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Semin Respir Crit Care Med 2021; 42(01): 020-039
DOI: 10.1055/s-0040-1713422
Review Article

Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome

Declan Byrnes‡   *
1   Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland
2   Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
,
Claire H. Masterson‡   *
1   Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland
2   Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
,
Antonio Artigas
3   Critical Care Center, Corporació Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain
,
John G. Laffey
1   Department of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland
2   Regenerative Medicine Institute (REMEDI), CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland
4   Department of Anaesthesia, SAOLTA University Health Group, Galway University Hospitals, Galway, Ireland
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Abstract

Sepsis and acute respiratory distress syndrome (ARDS) constitute devastating conditions with high morbidity and mortality. Sepsis results from abnormal host immune response, with evidence for both pro- and anti-inflammatory activation present from the earliest phases. The “proinflammatory” response predominates initially causing host injury, with later-phase sepsis characterized by immune cell hypofunction and opportunistic superinfection. ARDS is characterized by inflammation and disruption of the alveolar-capillary membrane leading to injury and lung dysfunction. Sepsis is the most common cause of ARDS. Approximately 20% of deaths worldwide in 2017 were due to sepsis, while ARDS occurs in over 10% of all intensive care unit patients and results in a mortality of 30 to 45%. Given the fact that sepsis and ARDS share some—but not all—underlying pathophysiologic injury mechanisms, the lack of specific therapies, and their frequent coexistence in the critically ill, it makes sense to consider therapies for both conditions together. In this article, we will focus on the therapeutic potential of mesenchymal stem/stromal cells (MSCs). MSCs are available from several tissues, including bone marrow, umbilical cord, and adipose tissue. Allogeneic administration is feasible, an important advantage for acute conditions like sepsis or ARDS. They possess diverse mechanisms of action of relevance to sepsis and ARDS, including direct and indirect antibacterial actions, potent effects on the innate and adaptive response, and pro-reparative effects. MSCs can be preactivated thereby potentiating their effects, while the use of their extracellular vesicles can avoid whole cell administration. While early-phase clinical trials suggest safety, considerable challenges exist in moving forward to phase III efficacy studies, and to implementation as a therapy should they prove effective.

Keywords

mesenchymal stem/stromal cells - sepsis - acute respiratory distress syndrome - immune response

* These authors contributed equally to the manuscript.




Publication History

Article published online:
06 August 2020

© 2020. Thieme. All rights reserved.

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  • References

  • 1 Bellani G, Laffey JG, Pham T. et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315 (08) 788-800
    Google Scholar
  • 2 Rudd KE, Johnson SC, Agesa KM. et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020; 395 (10219): 200-211
    CrossrefPubMedGoogle Scholar
  • 3 Marchant A, Devière J, Byl B, De Groote D, Vincent JL, Goldman M. Interleukin-10 production during septicaemia. Lancet 1994; 343 (8899): 707-708
    CrossrefPubMedGoogle Scholar
  • 4 Ding R, Meng Y, Ma X. The central role of the inflammatory response in understanding the heterogeneity of sepsis-3. BioMed Res Int 2018; 2018: 5086516
    CrossrefPubMedGoogle Scholar
  • 5 Delano MJ, Ward PA. The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev 2016; 274 (01) 330-353
    CrossrefPubMedGoogle Scholar
  • 6 Vincent JL, Sakr Y, Singer M. et al; EPIC III Investigators. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 2020; 323 (15) 1478-1487
    CrossrefPubMedGoogle Scholar
  • 7 Máca J, Jor O, Holub M. et al. Past and present ARDS mortality rates: a systematic review. Respir Care 2017; 62 (01) 113-122
    CrossrefPubMedGoogle Scholar
  • 8 McNicholas BA, Rooney GM, Laffey JG. Lessons to learn from epidemiologic studies in ARDS. Curr Opin Crit Care 2018; 24 (01) 41-48
    CrossrefPubMedGoogle Scholar
  • 9 Bersten AD, Edibam C, Hunt T, Moran J. Australian and New Zealand Intensive Care Society Clinical Trials Group. Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 2002; 165 (04) 443-448
    CrossrefPubMedGoogle Scholar
  • 10 Ranieri VM, Rubenfeld GD, Thompson BT. et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012; 307 (23) 2526-2533
    CrossrefPubMedGoogle Scholar
  • 11 Kon ZN, Dahi S, Evans CF. et al. Long-term venovenous extracorporeal membrane oxygenation support for acute respiratory distress syndrome. Ann Thorac Surg 2015; 100 (06) 2059-2063
    CrossrefPubMedGoogle Scholar
  • 12 Laffey JG, Kavanagh BP. Negative trials in critical care: why most research is probably wrong. Lancet Respir Med 2018; 6 (09) 659-660
    CrossrefPubMedGoogle Scholar
  • 13 Villar J, Ferrando C, Martínez D. et al; Dexamethasone in ARDS Network. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 2020; 8 (03) 267-276
    CrossrefPubMedGoogle Scholar
  • 14 Lyle NH, Pena OM, Boyd JH, Hancock RE. Barriers to the effective treatment of sepsis: antimicrobial agents, sepsis definitions, and host-directed therapies. Ann N Y Acad Sci 2014; 1323: 101-114
    CrossrefPubMedGoogle Scholar
  • 15 Mahida RY, Matsumoto S, Matthay MA. Extracellular vesicles: a new frontier for research in acute respiratory distress syndrome. Am J Respir Cell Mol Biol 2020; DOI: 10.1165/rcmb.2019-0447TR. (ePub online ahead of print)
    CrossrefPubMedGoogle Scholar
  • 16 Thomas ED, Buckner CD, Banaji M. et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49 (04) 511-533
    CrossrefPubMedGoogle Scholar
  • 17 Thomas ED. Bone marrow transplantation from the personal viewpoint. Int J Hematol 2005; 81 (02) 89-93
    CrossrefPubMedGoogle Scholar
  • 18 Dominici M, Le Blanc K, Mueller I. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8 (04) 315-317
    CrossrefPubMedGoogle Scholar
  • 19 Galipeau J, Krampera M, Barrett J. et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016; 18 (02) 151-159
    CrossrefPubMedGoogle Scholar
  • 20 Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplant 2011; 20 (01) 5-14
    CrossrefPubMedGoogle Scholar
  • 21 Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 2014; 32 (03) 252-260
    CrossrefPubMedGoogle Scholar
  • 22 Andrzejewska A, Lukomska B, Janowski M. Concise review: mesenchymal stem cells: from roots to boost. Stem Cells 2019; 37 (07) 855-864
    CrossrefPubMedGoogle Scholar
  • 23 dos Santos CC, Murthy S, Hu P. et al. Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. Am J Pathol 2012; 181 (05) 1681-1692
    CrossrefPubMedGoogle Scholar
  • 24 Silva JD, de Castro LL, Braga CL. et al. Mesenchymal stromal cells are more effective than their extracellular vesicles at reducing lung injury regardless of acute respiratory distress syndrome etiology. Stem Cells Int 2019; 2019: 8262849
    CrossrefPubMedGoogle Scholar
  • 25 Curley GF, Ansari B, Hayes M. et al. Effects of intratracheal mesenchymal stromal cell therapy during recovery and resolution after ventilator-induced lung injury. Anesthesiology 2013; 118 (04) 924-932
    CrossrefPubMedGoogle Scholar
  • 26 Hayes M, Curley GF, Masterson C, Devaney J, O'Toole D, Laffey JG. 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 (01) 29
    CrossrefPubMedGoogle Scholar
  • 27 Su VY-F, Yang K-Y. Mesenchymal stem cell-conditioned medium induces neutrophils apoptosis via inhibition of NF-kB pathway and increases endogenous pulmonary stem cells in endotoxin-induced acute lung injury. Eur Respir J 2015;46:suppl 59
    Google Scholar
  • 28 Ionescu L, Byrne RN, van Haaften T. et al. 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 (11) L967-L977
    CrossrefPubMedGoogle Scholar
  • 29 Lanyu Z, Feilong H. Emerging role of extracellular vesicles in lung injury and inflammation. Biomed Pharmacother 2019; 113: 108748
    CrossrefPubMedGoogle Scholar
  • 30 Monsel A, Zhu YG, Gennai S. et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med 2015; 192 (03) 324-336
    CrossrefPubMedGoogle Scholar
  • 31 Tang XD, Shi L, Monsel A. et al. Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA. Stem Cells 2017; 35 (07) 1849-1859
    CrossrefPubMedGoogle Scholar
  • 32 Hu S, Park J, Liu A. et al. Mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells. Stem Cells Transl Med 2018; 7 (08) 615-624
    CrossrefPubMedGoogle Scholar
  • 33 Xu G, Zhang L, Ren G. et al. Immunosuppressive properties of cloned bone marrow mesenchymal stem cells. Cell Res 2007; 17 (03) 240-248
    CrossrefPubMedGoogle Scholar
  • 34 Liu L, He H, Liu A. et al. Therapeutic effects of bone marrow-derived mesenchymal stem cells in models of pulmonary and extrapulmonary acute lung injury. Cell Transplant 2015; 24 (12) 2629-2642
    CrossrefPubMedGoogle Scholar
  • 35 Islam MN, Das SR, Emin MT. et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18 (05) 759-765
    CrossrefPubMedGoogle Scholar
  • 36 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 (08) 2210-2223
    CrossrefPubMedGoogle Scholar
  • 37 Abreu SC, Rolandsson Enes S, Dearborn J. et al. Lung inflammatory environments differentially alter mesenchymal stromal cell behavior. Am J Physiol Lung Cell Mol Physiol 2019; 317 (06) L823-L831
    CrossrefPubMedGoogle Scholar
  • 38 Xu AL, Rodriguez II LA, Walker III KP. et al. Mesenchymal stem cells reconditioned in their own serum exhibit augmented therapeutic properties in the setting of acute respiratory distress syndrome. Stem Cells Transl Med 2019; 8 (10) 1092-1106
    CrossrefPubMedGoogle Scholar
  • 39 Horie S, Gaynard S, Murphy M. et al. Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism. Intensive Care Med Exp 2020; 8 (01) 8
    CrossrefPubMedGoogle Scholar
  • 40 Cassatella MA, Mosna F, Micheletti A. et al. Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils. Stem Cells 2011; 29 (06) 1001-1011
    CrossrefPubMedGoogle Scholar
  • 41 Takeda K, Webb TL, Ning F. et al. Mesenchymal stem cells recruit CCR2+ monocytes to suppress allergic airway inflammation. J Immunol 2018; 200 (04) 1261-1269
    CrossrefPubMedGoogle Scholar
  • 42 Varkouhi AK, Jerkic M, Ormesher L. et al. Extracellular vesicles from interferon-γ-primed human umbilical cord mesenchymal stromal cells reduce Escherichia coli-induced acute lung injury in rats. Anesthesiology 2019; 130 (05) 778-790
    CrossrefPubMedGoogle Scholar
  • 43 Chang CL, Leu S, Sung HC. et al. Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in rat sepsis syndrome induced by cecal puncture and ligation. J Transl Med 2012; 10: 244
    CrossrefPubMedGoogle Scholar
  • 44 Chen HH, Chang CL, Lin KC. et al. Melatonin augments apoptotic adipose-derived mesenchymal stem cell treatment against sepsis-induced acute lung injury. Am J Transl Res 2014; 6 (05) 439-458
    PubMedGoogle Scholar
  • 45 Han J, Li Y, Li Y. Strategies to enhance mesenchymal stem cell-based therapies for acute respiratory distress syndrome. Stem Cells Int 2019; 2019: 5432134
    PubMedGoogle Scholar
  • 46 Yang JX, Zhang N, Wang HW, Gao P, Yang QP, Wen QP. CXCR4 receptor overexpression in mesenchymal stem cells facilitates treatment of acute lung injury in rats. J Biol Chem 2015; 290 (04) 1994-2006
    CrossrefPubMedGoogle Scholar
  • 47 Han J, Lu X, Zou L, Xu X, Qiu H. E-prostanoid 2 receptor overexpression promotes mesenchymal stem cell attenuated lung injury. Hum Gene Ther 2016; 27 (08) 621-630
    CrossrefPubMedGoogle Scholar
  • 48 Martínez-González I, Roca O, Masclans JR. et al. Human mesenchymal stem cells overexpressing the IL-33 antagonist soluble IL-1 receptor-like-1 attenuate endotoxin-induced acute lung injury. Am J Respir Cell Mol Biol 2013; 49 (04) 552-562
    CrossrefPubMedGoogle Scholar
  • 49 Li L, Dong L, Wang Y, Zhang X, Yan J. Lats1/2-mediated alteration of hippo signaling pathway regulates the fate of bone marrow-derived mesenchymal stem cells. BioMed Res Int 2018; 2018: 4387932
    PubMedGoogle Scholar
  • 50 Chen J, Li C, Gao X. et al. Keratinocyte growth factor gene delivery via mesenchymal stem cells protects against lipopolysaccharide-induced acute lung injury in mice. PLoS One 2013; 8 (12) e83303
    CrossrefPubMedGoogle Scholar
  • 51 Mei SH, McCarter SD, Deng Y, Parker CH, Liles WC, Stewart DJ. Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1. PLoS Med 2007; 4 (09) e269
    CrossrefPubMedGoogle Scholar
  • 52 Wang H, Yang YF, Zhao L. et al. Hepatocyte growth factor gene-modified mesenchymal stem cells reduce radiation-induced lung injury. Hum Gene Ther 2013; 24 (03) 343-353
    CrossrefPubMedGoogle Scholar
  • 53 Jin HJ, Bae YK, Kim M. et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci 2013; 14 (09) 17986-18001
    CrossrefPubMedGoogle Scholar
  • 54 Chen X, Wu S, Tang L. et al. Mesenchymal stem cells overexpressing heme oxygenase-1 ameliorate lipopolysaccharide-induced acute lung injury in rats. J Cell Physiol 2019; 234 (05) 7301-7319
    CrossrefPubMedGoogle Scholar
  • 55 Lu Z, Chang W, Meng S. et al. Mesenchymal stem cells induce dendritic cell immune tolerance via paracrine hepatocyte growth factor to alleviate acute lung injury. Stem Cell Res Ther 2019; 10 (01) 372
    CrossrefPubMedGoogle Scholar
  • 56 Jerkic M, Masterson C, Ormesher L. et al. Overexpression of IL-10 enhances the efficacy of human umbilical-cord-derived mesenchymal stromal cells in E. coli pneumosepsis. J Clin Med 2019; 8 (06) 8
    Google Scholar
  • 57 Zhang X, Chen J, Xue M. et al. Overexpressing p130/E2F4 in mesenchymal stem cells facilitates the repair of injured alveolar epithelial cells in LPS-induced ARDS mice. Stem Cell Res Ther 2019; 10 (01) 74
    CrossrefPubMedGoogle Scholar
  • 58 Liu D, Cao S, Zhou Y, Xiong Y. Recent advances in endotoxin tolerance. J Cell Biochem 2019; 120 (01) 56-70
    CrossrefPubMedGoogle Scholar
  • 59 Gupta N, Krasnodembskaya A, Kapetanaki M. et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax 2012; 67 (06) 533-539
    CrossrefPubMedGoogle Scholar
  • 60 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 (07) 625-635
    CrossrefPubMedGoogle Scholar
  • 61 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 (02) 363-373
    CrossrefPubMedGoogle Scholar
  • 62 Li X, Yue S, Luo Z. Mesenchymal stem cells in idiopathic pulmonary fibrosis. Oncotarget 2017; 8 (60) 102600-102616
    CrossrefPubMedGoogle Scholar
  • 63 Zanoni M, Cortesi M, Zamagni A, Tesei A. The role of mesenchymal stem cells in radiation-induced lung fibrosis. Int J Mol Sci 2019; 20 (16) 20
    Google Scholar
  • 64 Jung YJ, Park YY, Huh JW, Hong SB. The effect of human adipose-derived stem cells on lipopolysaccharide-induced acute respiratory distress syndrome in mice. Ann Transl Med 2019; 7 (22) 674
    CrossrefPubMedGoogle Scholar
  • 65 von Bahr V, Millar JE, Malfertheiner MV. et al. Mesenchymal stem cells may ameliorate inflammation in an ex vivo model of extracorporeal membrane oxygenation. Perfusion 2019; 34 (1, Suppl): 15-21
    CrossrefPubMedGoogle Scholar
  • 66 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 (01) 42-49
    CrossrefPubMedGoogle Scholar
  • 67 Chao YH, Wu HP, Wu KH. et al. An increase in CD3+CD4+CD25+ regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis. PLoS One 2014; 9 (10) e110338
    CrossrefPubMedGoogle Scholar
  • 68 Lee FY, Chen KH, Wallace CG. et al. Xenogeneic human umbilical cord-derived mesenchymal stem cells reduce mortality in rats with acute respiratory distress syndrome complicated by sepsis. Oncotarget 2017; 8 (28) 45626-45642
    CrossrefPubMedGoogle Scholar
  • 69 Gonzalez-Rey E, Anderson P, González MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 2009; 58 (07) 929-939
    CrossrefPubMedGoogle Scholar
  • 70 Pedrazza L, Lunardelli A, Luft C. et al. Mesenchymal stem cells decrease splenocytes apoptosis in a sepsis experimental model. Inflamm Res 2014; 63 (09) 719-728
    CrossrefPubMedGoogle Scholar
  • 71 Jerkic M, Gagnon S, Rabani R. et al. Human umbilical cord mesenchymal stromal cells attenuate systemic sepsis in part by enhancing peritoneal macrophage bacterial killing via heme oxygenase-1 induction in rats. Anesthesiology 2020; 132 (01) 140-154
    CrossrefPubMedGoogle Scholar
  • 72 Alcayaga-Miranda F, Cuenca J, Martin A, Contreras L, Figueroa FE, Khoury M. Combination therapy of menstrual derived mesenchymal stem cells and antibiotics ameliorates survival in sepsis. Stem Cell Res Ther 2015; 6: 199
    CrossrefPubMedGoogle Scholar
  • 73 Mei SH, Haitsma JJ, Dos Santos CC. et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med 2010; 182 (08) 1047-1057
    CrossrefPubMedGoogle Scholar
  • 74 Chiu S, Bharat A. Role of monocytes and macrophages in regulating immune response following lung transplantation. Curr Opin Organ Transplant 2016; 21 (03) 239-245
    CrossrefPubMedGoogle Scholar
  • 75 Ziegler-Heitbrock L, Ancuta P, Crowe S. et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116 (16) e74-e80
    CrossrefPubMedGoogle Scholar
  • 76 Wong KL, Tai JJ, Wong WC. et al. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 2011; 118 (05) e16-e31
    CrossrefPubMedGoogle Scholar
  • 77 Chimen M, Yates CM, McGettrick HM. et al. Monocyte subsets coregulate inflammatory responses by integrated signaling through TNF and IL-6 at the endothelial cell interface. J Immunol 2017; 198 (07) 2834-2843
    CrossrefPubMedGoogle Scholar
  • 78 Giesbrecht K, Eberle ME, Wölfle SJ. et al. IL-1β as mediator of resolution that reprograms human peripheral monocytes toward a suppressive phenotype. Front Immunol 2017; 8: 899
    CrossrefPubMedGoogle Scholar
  • 79 Varga G, Foell D. Anti-inflammatory monocytes-interplay of innate and adaptive immunity. Mol Cell Pediatr 2018; 5 (01) 5
    CrossrefPubMedGoogle Scholar
  • 80 Poehlmann H, Schefold JC, Zuckermann-Becker H, Volk HD, Meisel C. Phenotype changes and impaired function of dendritic cell subsets in patients with sepsis: a prospective observational analysis. Crit Care 2009; 13 (04) R119
    CrossrefPubMedGoogle Scholar
  • 81 Melief SM, Schrama E, Brugman MH. et al. Multipotent stromal cells induce human regulatory T cells through a novel pathway involving skewing of monocytes toward anti-inflammatory macrophages. Stem Cells 2013; 31 (09) 1980-1991
    CrossrefPubMedGoogle Scholar
  • 82 Deng Y, Zhang Y, Ye L. et al. Umbilical cord-derived mesenchymal stem cells instruct monocytes towards an IL10-producing phenotype by secreting IL6 and HGF. Sci Rep 2016; 6: 37566
    CrossrefPubMedGoogle Scholar
  • 83 Glass CK, Natoli G. Molecular control of activation and priming in macrophages. Nat Immunol 2016; 17 (01) 26-33
    CrossrefPubMedGoogle Scholar
  • 84 Aggarwal NR, King LS, D'Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 2014; 306 (08) L709-L725
    CrossrefPubMedGoogle Scholar
  • 85 Ortega-Gómez A, Perretti M, Soehnlein O. Resolution of inflammation: an integrated view. EMBO Mol Med 2013; 5 (05) 661-674
    CrossrefPubMedGoogle Scholar
  • 86 Braza F, Dirou S, Forest V. et al. Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells 2016; 34 (07) 1836-1845
    CrossrefPubMedGoogle Scholar
  • 87 Rabani R, Volchuk A, Jerkic M. et al. Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis. Eur Respir J 2018; 51 (04) 51
    Google Scholar
  • 88 Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13 (03) 159-175
    CrossrefPubMedGoogle Scholar
  • 89 Mantovani A, Cassatella MA, Costantini C, Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nat Rev Immunol 2011; 11 (08) 519-531
    CrossrefPubMedGoogle Scholar
  • 90 Matute-Bello G, Liles WC, Radella II F. et al. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 156 (06) 1969-1977
    CrossrefPubMedGoogle Scholar
  • 91 Potey PM, Rossi AG, Lucas CD, Dorward DA. Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. J Pathol 2019; 247 (05) 672-685
    CrossrefPubMedGoogle Scholar
  • 92 Luan YY, Yao YM, Xiao XZ, Sheng ZY. Insights into the apoptotic death of immune cells in sepsis. J Interferon Cytokine Res 2015; 35 (01) 17-22
    CrossrefPubMedGoogle Scholar
  • 93 Nourshargh S, Renshaw SA, Imhof BA. Reverse migration of neutrophils: Where, when, how, and why?. Trends Immunol 2016; 37 (05) 273-286
    CrossrefPubMedGoogle Scholar
  • 94 Joel MDM, Yuan J, Wang J. et al. MSC: immunoregulatory effects, roles on neutrophils and evolving clinical potentials. Am J Transl Res 2019; 11 (06) 3890-3904
    PubMedGoogle Scholar
  • 95 Su VY, Lin CS, Hung SC, Yang KY. Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κB pathway in endotoxin-induced acute lung injury. Int J Mol Sci 2019; 20 (09) 20
    Google Scholar
  • 96 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 (12) 3552-3564
    CrossrefPubMedGoogle Scholar
  • 97 Hu S, He W, Du X. et al. IL-17 production of neutrophils enhances antibacteria ability but promotes arthritis development during mycobacterium tuberculosis infection. EBioMedicine 2017; 23: 88-99
    CrossrefPubMedGoogle Scholar
  • 98 Morrow KN, Coopersmith CM, Ford ML. IL-17, IL-27, and IL-33: a novel axis linked to immunological dysfunction during sepsis. Front Immunol 2019; 10: 1982
    CrossrefPubMedGoogle Scholar
  • 99 Hall SR, Tsoyi K, Ith B. et al. Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils. Stem Cells 2013; 31 (02) 397-407
    CrossrefPubMedGoogle Scholar
  • 100 Jiang D, Muschhammer J, Qi Y. et al. Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem cells. Stem Cells 2016; 34 (09) 2393-2406
    CrossrefPubMedGoogle Scholar
  • 101 Nguyen HX, Hooshmand MJ, Saiwai H. et al. Systemic neutrophil depletion modulates the migration and fate of transplanted human neural stem cells to rescue functional repair. J Neurosci 2017; 37 (38) 9269-9287
    CrossrefPubMedGoogle Scholar
  • 102 Zhang Z, Tian H, Yang C. et al. Mesenchymal stem cells promote the resolution of cardiac inflammation after ischemia reperfusion via enhancing efferocytosis of neutrophils. J Am Heart Assoc 2020; 9 (05) e014397
    CrossrefPubMedGoogle Scholar
  • 103 Reis e Sousa C. Dendritic cells in a mature age. Nat Rev Immunol 2006; 6 (06) 476-483
    CrossrefPubMedGoogle Scholar
  • 104 Steinbrink K, Graulich E, Kubsch S, Knop J, Enk AH. CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 2002; 99 (07) 2468-2476
    CrossrefPubMedGoogle Scholar
  • 105 Li Y, Wang W, Yang F, Xu Y, Feng C, Zhao Y. The regulatory roles of neutrophils in adaptive immunity. Cell Commun Signal 2019; 17 (01) 147
    CrossrefPubMedGoogle Scholar
  • 106 Harizi H, Gualde N. Pivotal role of PGE2 and IL-10 in the cross-regulation of dendritic cell-derived inflammatory mediators. Cell Mol Immunol 2006; 3 (04) 271-277
    PubMedGoogle Scholar
  • 107 Shahir M, Mahmoud Hashemi S, Asadirad A. et al. Effect of mesenchymal stem cell-derived exosomes on the induction of mouse tolerogenic dendritic cells. J Cell Physiol 2020
    Google Scholar
  • 108 Jiang XX, Zhang Y, Liu B. et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 2005; 105 (10) 4120-4126
    CrossrefPubMedGoogle Scholar
  • 109 Janeway CA, Walport M. et al. The complement system and innate immunity. In: Immunobiology. The Immune System in Health and Disease. 5th ed. New York: Garland Science; 2001: 61-83
    Google Scholar
  • 110 Strunk RC, Eidlen DM, Mason RJ. Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways. J Clin Invest 1988; 81 (05) 1419-1426
    CrossrefPubMedGoogle Scholar
  • 111 Varsano S, Kaminsky M, Kaiser M, Rashkovsky L. Generation of complement C3 and expression of cell membrane complement inhibitory proteins by human bronchial epithelium cell line. Thorax 2000; 55 (05) 364-369
    CrossrefPubMedGoogle Scholar
  • 112 Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS. Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value. Lancet 1980; 1 (8175): 947-949
    CrossrefPubMedGoogle Scholar
  • 113 Zilow G, Sturm JA, Rother U, Kirschfink M. Complement activation and the prognostic value of C3a in patients at risk of adult respiratory distress syndrome. Clin Exp Immunol 1990; 79 (02) 151-157
    CrossrefPubMedGoogle Scholar
  • 114 Harkin DW, Romaschin A, Taylor SM, Rubin BB, Lindsay TF. Complement C5a receptor antagonist attenuates multiple organ injury in a model of ruptured abdominal aortic aneurysm. J Vasc Surg 2004; 39 (01) 196-206
    CrossrefPubMedGoogle Scholar
  • 115 Harkin DW, Marron CD, Rother RP, Romaschin A, Rubin BB, Lindsay TF. C5 complement inhibition attenuates shock and acute lung injury in an experimental model of ruptured abdominal aortic aneurysm. Br J Surg 2005; 92 (10) 1227-1234
    CrossrefPubMedGoogle Scholar
  • 116 Gralinski LE, Sheahan TP, Morrison TE. et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio 2018; 9 (05) 9
    Google Scholar
  • 117 Charchaflieh J, Wei J, Labaze G. et al. The role of complement system in septic shock. Clin Dev Immunol 2012; 2012: 407324
    CrossrefPubMedGoogle Scholar
  • 118 Moll G, Jitschin R, von Bahr L. et al. Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PLoS One 2011; 6 (07) e21703
    CrossrefPubMedGoogle Scholar
  • 119 Tu Z, Li Q, Bu H, Lin F. Mesenchymal stem cells inhibit complement activation by secreting factor H. Stem Cells Dev 2010; 19 (11) 1803-1809
    CrossrefPubMedGoogle Scholar
  • 120 de Pablo R, Monserrat J, Prieto A, Alvarez-Mon M. Role of circulating lymphocytes in patients with sepsis. BioMed Res Int 2014; 2014: 671087
    CrossrefPubMedGoogle Scholar
  • 121 Heuer JG, Zhang T, Zhao J. et al. Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. J Immunol 2005; 174 (11) 7141-7146
    CrossrefPubMedGoogle Scholar
  • 122 Kühlhorn F, Rath M, Schmoeckel K. et al. Foxp3+ regulatory T cells are required for recovery from severe sepsis. PLoS One 2013; 8 (05) e65109
    CrossrefPubMedGoogle Scholar
  • 123 Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005; 105 (04) 1815-1822
    CrossrefPubMedGoogle Scholar
  • 124 Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther 2011; 2 (04) 34
    CrossrefPubMedGoogle Scholar
  • 125 Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol 2019; 10: 1191
    Google Scholar
  • 126 Tobón GJ, Izquierdo JH, Cañas CA. B lymphocytes: development, tolerance, and their role in autoimmunity-focus on systemic lupus erythematosus. Autoimmune Dis 2013; 2013: 827254
    PubMedGoogle Scholar
  • 127 Monserrat J, de Pablo R, Diaz-Martín D. et al. Early alterations of B cells in patients with septic shock. Crit Care 2013; 17 (03) R105
    CrossrefPubMedGoogle Scholar
  • 128 Gustave CA, Gossez M, Demaret J. et al. Septic shock shapes B cell response toward an exhausted-like/immunoregulatory profile in patients. J Immunol 2018; 200 (07) 2418-2425
    CrossrefPubMedGoogle Scholar
  • 129 Moir S, Malaspina A, Ho J. et al. Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis 2008; 197 (04) 572-579
    CrossrefPubMedGoogle Scholar
  • 130 Doi H, Tanoue S, Kaplan DE. Peripheral CD27-CD21- B-cells represent an exhausted lymphocyte population in hepatitis C cirrhosis. Clin Immunol 2014; 150 (02) 184-191
    CrossrefPubMedGoogle Scholar
  • 131 Suzuki K, Inoue S, Kametani Y. et al. Reduced immunocompetent B cells and increased secondary infection in elderly patients with severe sepsis. Shock 2016; 46 (03) 270-278
    CrossrefPubMedGoogle Scholar
  • 132 Franquesa M, Mensah FK, Huizinga R. et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells 2015; 33 (03) 880-891
    CrossrefPubMedGoogle Scholar
  • 133 Carreras-Planella L, Monguió-Tortajada M, Borràs FE, Franquesa M. Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front Immunol 2019; 10: 1288
    CrossrefPubMedGoogle Scholar
  • 134 Luk F, Carreras-Planella L, Korevaar SS. et al. Inflammatory conditions dictate the effect of mesenchymal stem or stromal cells on B cell function. Front Immunol 2017; 8: 1042
    CrossrefPubMedGoogle Scholar
  • 135 Franquesa M, Hoogduijn MJ, Bestard O, Grinyó JM. Immunomodulatory effect of mesenchymal stem cells on B cells. Front Immunol 2012; 3: 212
    CrossrefPubMedGoogle Scholar
  • 136 Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial activity of mesenchymal stem cells: current status and new perspectives of antimicrobial peptide-based therapies. Front Immunol 2017; 8: 339
    Google Scholar
  • 137 Duplantier AJ, van Hoek ML. The human cathelicidin antimicrobial peptide LL-37 as a potential treatment for polymicrobial infected wounds. Front Immunol 2013; 4: 143
    CrossrefPubMedGoogle Scholar
  • 138 Wang G, Li X, Wang Z. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Res 2016; 44 (D1): D1087-D1093
    CrossrefPubMedGoogle Scholar
  • 139 Zhang LJ, Gallo RL. Antimicrobial peptides. Curr Biol 2016; 26 (01) R14-R19
    CrossrefPubMedGoogle Scholar
  • 140 Bergman P, Walter-Jallow L, Broliden K, Agerberth B, Söderlund J. The antimicrobial peptide LL-37 inhibits HIV-1 replication. Curr HIV Res 2007; 5 (04) 410-415
    CrossrefPubMedGoogle Scholar
  • 141 Currie SM, Gwyer Findlay E, McFarlane AJ. et al. Cathelicidins have direct antiviral activity against respiratory syncytial virus in vitro and protective function in vivo in mice and humans. J Immunol 2016; 196 (06) 2699-2710
    CrossrefPubMedGoogle Scholar
  • 142 Hsieh IN, Hartshorn KL. The role of antimicrobial peptides in influenza virus infection and their potential as antiviral and immunomodulatory therapy. Pharmaceuticals (Basel) 2016; 9 (03) 9
    CrossrefPubMedGoogle Scholar
  • 143 Shahmiri M, Enciso M, Adda CG, Smith BJ, Perugini MA, Mechler A. Membrane core-specific antimicrobial action of cathelicidin LL-37 peptide switches between pore and nanofibre formation. Sci Rep 2016; 6: 38184
    CrossrefPubMedGoogle Scholar
  • 144 Niyonsaba F, Iwabuchi K, Someya A. et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology 2002; 106 (01) 20-26
    CrossrefPubMedGoogle Scholar
  • 145 Mookherjee N, Wilson HL, Doria S. et al. Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide. J Leukoc Biol 2006; 80 (06) 1563-1574
    CrossrefPubMedGoogle Scholar
  • 146 Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol 2013; 191 (10) 4895-4901
    CrossrefPubMedGoogle Scholar
  • 147 Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun 2008; 76 (09) 4176-4182
    CrossrefPubMedGoogle Scholar
  • 148 Cirioni O, Giacometti A, Ghiselli R. et al. LL-37 protects rats against lethal sepsis caused by gram-negative bacteria. Antimicrob Agents Chemother 2006; 50 (05) 1672-1679
    CrossrefPubMedGoogle Scholar
  • 149 Krasnodembskaya A, Song Y, Fang X. et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 2010; 28 (12) 2229-2238
    CrossrefPubMedGoogle Scholar
  • 150 Curley GF, Jerkic M, Dixon S. et al. Cryopreserved, Xeno-free human umbilical cord mesenchymal stromal cells reduce lung injury severity and bacterial burden in rodent Escherichia coli-induced acute respiratory distress syndrome. Crit Care Med 2017; 45 (02) e202-e212
    CrossrefPubMedGoogle Scholar
  • 151 Hao Q, Gudapati V, Monsel A. et al. Mesenchymal stem cell-derived extracellular vesicles decrease lung injury in mice. J Immunol 2019; 203 (07) 1961-1972
    CrossrefPubMedGoogle Scholar
  • 152 Arman M, Krauel K, Tilley DO. et al. Amplification of bacteria-induced platelet activation is triggered by FcγRIIA, integrin αIIbβ3, and platelet factor 4. Blood 2014; 123 (20) 3166-3174
    CrossrefPubMedGoogle Scholar
  • 153 Sharma B, Sharma M, Majumder M, Steier W, Sangal A, Kalawar M. Thrombocytopenia in septic shock patients--a prospective observational study of incidence, risk factors and correlation with clinical outcome. Anaesth Intensive Care 2007; 35 (06) 874-880
    CrossrefPubMedGoogle Scholar
  • 154 Assinger A, Schrottmaier WC, Salzmann M, Rayes J. Platelets in sepsis: an update on experimental models and clinical data. Front Immunol 2019; 10: 1687
    CrossrefPubMedGoogle Scholar
  • 155 Yadav H, Kor DJ. Platelets in the pathogenesis of acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2015; 309 (09) L915-L923
    CrossrefPubMedGoogle Scholar
  • 156 Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest 2006; 116 (12) 3211-3219
    CrossrefPubMedGoogle Scholar
  • 157 Yiming MT, Lederer DJ, Sun L, Huertas A, Issekutz AC, Bhattacharya S. Platelets enhance endothelial adhesiveness in high tidal volume ventilation. Am J Respir Cell Mol Biol 2008; 39 (05) 569-575
    CrossrefPubMedGoogle Scholar
  • 158 Stephenne X, Nicastro E, Eeckhoudt S. et al. Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity. PLoS One 2012; 7 (08) e42819
    CrossrefPubMedGoogle Scholar
  • 159 Tatsumi K, Ohashi K, Matsubara Y. et al. Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun 2013; 431 (02) 203-209
    CrossrefPubMedGoogle Scholar
  • 160 Gleeson BM, Martin K, Ali MT. et al. Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by antithrombin therapy. Stem Cells 2015; 33 (09) 2726-2737
    CrossrefPubMedGoogle Scholar
  • 161 George MJ, Prabhakara K, Toledano-Furman NE. et al. Clinical cellular therapeutics accelerate clot formation. Stem Cells Transl Med 2018; 7 (10) 731-739
    CrossrefPubMedGoogle Scholar
  • 162 Perlee D, de Vos AF, Scicluna BP. et al. Role of tissue factor in the procoagulant and antibacterial effects of human adipose-derived mesenchymal stem cells during pneumosepsis in mice. Stem Cell Res Ther 2019; 10 (01) 286
    CrossrefPubMedGoogle Scholar
  • 163 Netsch P, Elvers-Hornung S, Uhlig S. et al. Human mesenchymal stromal cells inhibit platelet activation and aggregation involving CD73-converted adenosine. Stem Cell Res Ther 2018; 9 (01) 184
    CrossrefPubMedGoogle Scholar
  • 164 Neuss S, Schneider RK, Tietze L, Knüchel R, Jahnen-Dechent W. Secretion of fibrinolytic enzymes facilitates human mesenchymal stem cell invasion into fibrin clots. Cells Tissues Organs 2010; 191 (01) 36-46
    CrossrefPubMedGoogle Scholar
  • 165 Chabot V, Dromard C, Rico A. et al. Urokinase-type plasminogen activator receptor interaction with β1 integrin is required for platelet-derived growth factor-AB-induced human mesenchymal stem/stromal cell migration. Stem Cell Res Ther 2015; 6: 188
    CrossrefPubMedGoogle Scholar
  • 166 Heissig B, Dhahri D, Eiamboonsert S. et al. Role of mesenchymal stem cell-derived fibrinolytic factor in tissue regeneration and cancer progression. Cell Mol Life Sci 2015; 72 (24) 4759-4770
    CrossrefPubMedGoogle Scholar
  • 167 Kim CF, Jackson EL, Woolfenden AE. et al. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 2005; 121 (06) 823-835
    CrossrefPubMedGoogle Scholar
  • 168 Lee JH, Bhang DH, Beede A. et al. Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 2014; 156 (03) 440-455
    CrossrefPubMedGoogle Scholar
  • 169 Leeman KT, Pessina P, Lee JH, Kim CF. Mesenchymal stem cells increase alveolar differentiation in lung progenitor organoid cultures. Sci Rep 2019; 9 (01) 6479
    CrossrefPubMedGoogle Scholar
  • 170 Tropea KA, Leder E, Aslam M. et al. Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012; 302 (09) L829-L837
    CrossrefPubMedGoogle Scholar
  • 171 Liu K, Tang M, Liu Q. et al. Bi-directional differentiation of single bronchioalveolar stem cells during lung repair. Cell Discov 2020; 6: 1
    CrossrefPubMedGoogle Scholar
  • 172 Srour N, Thébaud B. Mesenchymal stromal cells in animal bleomycin pulmonary fibrosis models: a systematic review. Stem Cells Transl Med 2015; 4 (12) 1500-1510
    CrossrefPubMedGoogle Scholar
  • 173 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. J Biol Chem 2010; 285 (34) 26211-26222
    CrossrefPubMedGoogle Scholar
  • 174 Qiao L, Hu S, Liu S. et al. microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential. J Clin Invest 2019; 129 (06) 2237-2250
    CrossrefPubMedGoogle Scholar
  • 175 Pill K, Hofmann S, Redl H, Holnthoner W. Vascularization mediated by mesenchymal stem cells from bone marrow and adipose tissue: a comparison. Cell Regen (Lond) 2015; 4: 8
    PubMedGoogle Scholar
  • 176 Bianco P, Cao X, Frenette PS. et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 2013; 19 (01) 35-42
    CrossrefPubMedGoogle Scholar
  • 177 Thompson M, Mei SHJ, Wolfe D. et al. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: an updated systematic review and meta-analysis. EClinicalMedicine 2020; 19: 100249
    Google Scholar
  • 178 Nasef A, Mathieu N, Chapel A. et al. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 2007; 84 (02) 231-237
    CrossrefPubMedGoogle Scholar
  • 179 McAuley DF, Curley GF, Hamid UI. et al. 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 (09) L809-L815
    CrossrefPubMedGoogle Scholar
  • 180 Hosseinikia R, Nikbakht MR, Moghaddam AA. et al. Molecular and cellular interactions of allogenic and autologous mesenchymal stem cells with innate and acquired immunity and their role in regenerative medicine. Int J Hematol Oncol Stem Cell Res 2017; 11 (01) 63-77
    PubMedGoogle Scholar
  • 181 Huang R, Qin C, Wang J. et al. Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury. Aging (Albany NY) 2019; 11 (18) 7996-8014
    CrossrefPubMedGoogle Scholar
  • 182 Mehrian M, Lambrechts T, Marechal M, Luyten FP, Papantoniou I, Geris L. Predicting in vitro human mesenchymal stromal cell expansion based on individual donor characteristics using machine learning. Cytotherapy 2020; 22 (02) 82-90
    CrossrefPubMedGoogle Scholar
  • 183 Trivedi A, Miyazawa B, Gibb S. et al. Bone marrow donor selection and characterization of MSCs is critical for pre-clinical and clinical cell dose production. J Transl Med 2019; 17 (01) 128
    CrossrefPubMedGoogle Scholar
  • 184 Cardenes N, Aranda-Valderrama P, Carney JP. et al. Cell therapy for ARDS: efficacy of endobronchial versus intravenous administration and biodistribution of MAPCs in a large animal model. BMJ Open Respir Res 2019; 6 (01) e000308
    Google Scholar
  • 185 Gonçalves FdaC, Schneider N, Pinto FO. et al. Intravenous vs intraperitoneal mesenchymal stem cells administration: what is the best route for treating experimental colitis?. World J Gastroenterol 2014; 20 (48) 18228-18239
    CrossrefPubMedGoogle Scholar
  • 186 McCarthy SD, Horgan E, Ali A. et al. Nebulized mesenchymal stem cell derived conditioned medium retains antibacterial properties against clinical pathogen isolates. J Aerosol Med Pulm Drug Deliv 2020; 33 (00) 1-13
    CrossrefPubMedGoogle Scholar
  • 187 Horie S, Masterson C, Brady J. et al. Umbilical cord-derived CD362+ mesenchymal stromal cells for E. coli pneumonia: impact of dose regimen, passage, cryopreservation, and antibiotic therapy. Stem Cell Res Ther 2020; 11 (01) 116
    CrossrefPubMedGoogle Scholar
  • 188 Eliopoulos N, Stagg J, Lejeune L, Pommey S, Galipeau J. Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 2005; 106 (13) 4057-4065
    CrossrefPubMedGoogle Scholar
  • 189 Farini A, Sitzia C, Erratico S, Meregalli M, Torrente Y. Clinical applications of mesenchymal stem cells in chronic diseases. Stem Cells Int 2014; 2014: 306573
    CrossrefPubMedGoogle Scholar
  • 190 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 (02) 154-162
    CrossrefPubMedGoogle Scholar
  • 191 Fujita Y, Nishimura M, Komori NW. et al. A pair of cell preservation solutions for therapy with human adipose tissue-derived mesenchymal stromal cells. Regen Ther 2020; 14: 95-102
    CrossrefPubMedGoogle Scholar
  • 192 Dodson BP, Levine AD. Challenges in the translation and commercialization of cell therapies. BMC Biotechnol 2015; 15: 70
    CrossrefPubMedGoogle Scholar
  • 193 Mizukami A, Swiech K. Mesenchymal stromal cells: from discovery to manufacturing and commercialization. Stem Cells Int 2018; 2018: 4083921
    CrossrefPubMedGoogle Scholar
  • 194 Kocyildirim E, Cárdenes N, Ting A, Cáceres E, BermUdez C, Rojas M. The use of GMP-produced bone marrow-derived stem cells in combination with extracorporeal membrane oxygenation in ARDS: an animal model. ASAIO J 2017; 63 (03) 324-332
    CrossrefPubMedGoogle Scholar
  • 195 Olajuyin AM, Zhang X, Ji HL. Alveolar type 2 progenitor cells for lung injury repair. Cell Death Discov 2019; 5: 63
    CrossrefPubMedGoogle Scholar
  • 196 Chen CH, Chen YL, Sung PH. et al. Effective protection against acute respiratory distress syndrome/sepsis injury by combined adipose-derived mesenchymal stem cells and preactivated disaggregated platelets. Oncotarget 2017; 8 (47) 82415-82429
    CrossrefPubMedGoogle Scholar
  • 197 Chimenti L, Camprubí-Rimblas M, Guillamat-Prats R. et al. Nebulized heparin attenuates pulmonary coagulopathy and inflammation through alveolar macrophages in a rat model of acute lung injury. Thromb Haemost 2017; 117 (11) 2125-2134
    Article in Thieme ConnectPubMedGoogle Scholar
  • 198 Ding Q, Liu G, Zeng Y. et al. Glycogen synthase kinase–3β inhibitor reduces LPS–induced acute lung injury in mice. Mol Med Rep 2017; 16 (05) 6715-6721
    CrossrefPubMedGoogle Scholar
  • 199 Zhang Z, Li W, Heng Z. et al. Combination therapy of human umbilical cord mesenchymal stem cells and FTY720 attenuates acute lung injury induced by lipopolysaccharide in a murine model. Oncotarget 2017; 8 (44) 77407-77414
    CrossrefPubMedGoogle Scholar
  • 200 Caplan AI. Cell-based therapies: the nonresponder. Stem Cells Transl Med 2018; 7 (11) 762-766
    CrossrefPubMedGoogle Scholar
  • 201 Davenport EE, Burnham KL, Radhakrishnan J. et al. Genomic landscape of the individual host response and outcomes in sepsis: a prospective cohort study. Lancet Respir Med 2016; 4 (04) 259-271
    CrossrefPubMedGoogle Scholar
  • 202 Scicluna BP, van Vught LA, Zwinderman AH. et al; MARS Consortium. Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study. Lancet Respir Med 2017; 5 (10) 816-826
    CrossrefPubMedGoogle Scholar
  • 203 Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA. NHLBI ARDS Network. Subphenotypes in acute respiratory distress syndrome: latent class analysis of data from two randomised controlled trials. Lancet Respir Med 2014; 2 (08) 611-620
    CrossrefPubMedGoogle Scholar
  • 204 McAuley DF, Laffey JG, O'Kane CM. et al; HARP-2 Investigators, Irish Critical Care Trials Group. Simvastatin in the acute respiratory distress syndrome. N Engl J Med 2014; 371 (18) 1695-1703
    CrossrefPubMedGoogle Scholar
  • 205 Calfee CS, Delucchi KL, Sinha P. et al; Irish Critical Care Trials Group. Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. Lancet Respir Med 2018; 6 (09) 691-698
    CrossrefPubMedGoogle Scholar
  • 206 Bos LD, Schouten LR, van Vught LA. et al; MARS Consortium. Identification and validation of distinct biological phenotypes in patients with acute respiratory distress syndrome by cluster analysis. Thorax 2017; 72 (10) 876-883
    CrossrefPubMedGoogle Scholar
  • 207 Christie JD, Wurfel MM, Feng R. et al; Trauma ALI SNP Consortium (TASC) investigators. Genome wide association identifies PPFIA1 as a candidate gene for acute lung injury risk following major trauma. PLoS One 2012; 7 (01) e28268
    CrossrefPubMedGoogle Scholar
  • 208 Dolinay T, Kim YS, Howrylak J. et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med 2012; 185 (11) 1225-1234
    CrossrefPubMedGoogle Scholar
  • 209 Bime C, Casanova N, Oita RC. et al. Development of a biomarker mortality risk model in acute respiratory distress syndrome. Crit Care 2019; 23 (01) 410
    CrossrefPubMedGoogle Scholar
  • 210 Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 2012; 8 (11) 622-633
    CrossrefPubMedGoogle Scholar
  • 211 Xu H, Chen M. Targeting the complement system for the management of retinal inflammatory and degenerative diseases. Eur J Pharmacol 2016; 787: 94-104
    CrossrefPubMedGoogle Scholar
  • 212 Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010; 5 (04) e10088
    CrossrefPubMedGoogle Scholar
  • 213 Saeedi P, Halabian R, Fooladi AAI. Antimicrobial effects of mesenchymal stem cells primed by modified LPS on bacterial clearance in sepsis. J Cell Physiol 2019; 234 (04) 4970-4986
    CrossrefPubMedGoogle Scholar
  • 214 Park J, Kim S, Lim H. et al. Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E. coli pneumonia. Thorax 2019; 74 (01) 43-50
    CrossrefPubMedGoogle Scholar
  • 215 Zhao X, Liu D, Gong W. et al. The toll-like receptor 3 ligand, poly(I:C), improves immunosuppressive function and therapeutic effect of mesenchymal stem cells on sepsis via inhibiting MiR-143. Stem Cells 2014; 32 (02) 521-533
    CrossrefPubMedGoogle Scholar
  • 216 Liu YY, Chiang CH, Hung SC. et al. Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury. PLoS One 2017; 12 (11) e0187637
    CrossrefPubMedGoogle Scholar
  • 217 Almeria C, Weiss R, Roy M. et al. Hypoxia conditioned mesenchymal stem cell-derived extracellular vesicles induce increased vascular tube formation in vitro . Front Bioeng Biotechnol 2019; 7: 292
    CrossrefPubMedGoogle Scholar
  • 218 Roemeling-van Rhijn M, Mensah FK, Korevaar SS. et al. Effects of hypoxia on the immunomodulatory properties of adipose tissue-derived mesenchymal stem cells. Front Immunol 2013; 4: 203
    CrossrefPubMedGoogle Scholar
  • 219 Song Y, Dou H, Li X. et al. Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1β-primed mesenchymal stem cells against sepsis. Stem Cells 2017; 35 (05) 1208-1221
    CrossrefPubMedGoogle Scholar
  • 220 Sivanathan KN, Rojas-Canales DM, Hope CM. et al. Interleukin-17A-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells 2015; 33 (09) 2850-2863
    CrossrefPubMedGoogle Scholar
  • 221 Han X, Yang Q, Lin L. et al. Interleukin-17 enhances immunosuppression by mesenchymal stem cells. Cell Death Differ 2014; 21 (11) 1758-1768
    CrossrefPubMedGoogle Scholar
  • 222 François M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 2012; 20 (01) 187-195
    CrossrefPubMedGoogle Scholar
  • 223 Yi X, Wei X, Lv H. et al. Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3. Exp Cell Res 2019; 383 (02) 111454
    CrossrefPubMedGoogle Scholar
  • 224 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 (01) 24-32
    CrossrefPubMedGoogle Scholar
  • 225 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
    CrossrefPubMedGoogle Scholar
  • 226 Bellingan G, Jacono F, Bannard-Smith J. et al. Primary Analysis of a Phase 1/2 Study to Assess MultiStem® Cell Therapy, a Regenerative Advanced Therapy Medicinal Product (ATMP), in Acute Respiratory Distress Syndrome (MUST-ARDS). Dallas TX: American Thoracic Society; 2019
    CrossrefGoogle Scholar
  • 227 Galstian GM, Parovichnikova EN, Makarova PM. et al. The results of the Russian Clinical Trial of Mesenchymal Stromal Cells (MSCs) in severe neutropenic patients (pts) with septic shock (SS) (RUMCESS trial). Blood 2015; 126 (23) 2220
    CrossrefPubMedGoogle Scholar
  • 228 Perlee D, van Vught LA, Scicluna BP. et al. Intravenous infusion of human adipose mesenchymal stem cells modifies the host response to lipopolysaccharide in humans: a randomized, single-blind, parallel group, placebo controlled trial. Stem Cells 2018; 36 (11) 1778-1788
    CrossrefPubMedGoogle Scholar