Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients

Christopher J Rogers, Robert J Harman, Bruce A Bunnell, Martin A Schreiber, Charlie Xiang, Fu-Sheng Wang, Antonio F Santidrian, Boris R Minev, Christopher J Rogers, Robert J Harman, Bruce A Bunnell, Martin A Schreiber, Charlie Xiang, Fu-Sheng Wang, Antonio F Santidrian, Boris R Minev

Abstract

In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.

Keywords: ARDS; COVID-19; Mesenchymal stem cells; Pneumonia; SARS-CoV-2.

Conflict of interest statement

CR, RH declared equity in Personalized Stem Cells, Inc., but there is no conflict of interest. The other authors indicated no potential conflicts of interest.

References

    1. Shi Y, Su J, Roberts AI, Shou P, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33(3):136–143.
    1. Harrell CR, Sadikot R, Pascual J, Fellabaum C, Jankovic MG, Jovicic N, et al. Mesenchymal stem cell-based therapy of inflammatory lung diseases: current understanding and future perspectives. Stem cells international. 2019;2019:4236973.
    1. Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW, 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.
    1. Khatri M, Richardson LA, Meulia T. Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model. Stem Cell Res Therapy. 2018;9(1):17.
    1. Hosseini M, Yousefifard M, Aziznejad H, Nasirinezhad F. The effect of bone marrow-derived mesenchymal stem cell transplantation on allodynia and hyperalgesia in neuropathic animals: a systematic review with meta-analysis. Biol Blood Marrow Transplant. 2015;21(9):1537–1544.
    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506.
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan. Jama: China; 2020.
    1. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med. 2020;382:1199–1207.
    1. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020;11:216–228.
    1. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565–574.
    1. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020;579(7798):270–273.
    1. Hoffmann M, Kleine-Weber H, Krüger N, Müller M, Drosten C, Pöhlmann S. The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. bioRxiv. 2020 doi: 10.1101/2020.01.31.929042.
    1. Organization WH. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19) 2020. . Accessed 24 Feb 2020.
    1. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420–422.
    1. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334–1349.
    1. Donahoe M. Acute respiratory distress syndrome: a clinical review. Pulm Circ. 2011;1(2):192–211.
    1. Baron RM, Levy BD. Recent advances in understanding and treating ARDS [version 1; referees: 2 approved] F1000Res. 2016;5(F1000 Faculty Rev):725. doi: 10.12688/f1000research.7646.1.
    1. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA. 2012;307(23):2526–2533.
    1. Herridge MS, Tansey CM, Matte A, Tomlinson G, Diaz-Granados N, Cooper A, et al. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364(14):1293–1304.
    1. Karbing DS, Kjaergaard S, Smith BW, Espersen K, Allerod C, Andreassen S, et al. Variation in the PaO2/FiO2 ratio with FiO2: mathematical and experimental description, and clinical relevance. Crit Care. 2007;11(6):R118.
    1. Hughes KT, Beasley MB. Pulmonary manifestations of acute lung injury: more than just diffuse alveolar damage. Arch Pathol Lab Med. 2017;141(7):916–922.
    1. Horie S, Gonzalez HE, Laffey JG, Masterson CH. Cell therapy in acute respiratory distress syndrome. J Thorac Dis. 2018;10(9):5607–5620.
    1. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–175.
    1. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159–2168.
    1. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107–1116.
    1. Tonelli AR, Zein J, Adams J, Ioannidis JP. Effects of interventions on survival in acute respiratory distress syndrome: an umbrella review of 159 published randomized trials and 29 meta-analyses. Intensive Care Med. 2014;40(6):769–787.
    1. Duggal AGA, Ratnapalan M, et al. Pharmacological treatments for acute respiratory distress syndrome: systematic review. Minera Anest. 2015;81:567–588.
    1. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6(2):230–247.
    1. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–650.
    1. Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–395.
    1. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317.
    1. Caplan AI. Mesenchymal stem cells: time to change the name! Stem cells Transl Med. 2017;6(6):1445–1451.
    1. Mazini L, Rochette L, Amine M, Malka G. Regenerative capacity of adipose derived stem cells (ADSCs), comparison with mesenchymal stem cells (MSCs) Int J Mol Sci. 2019;20(10):2523.
    1. Dufrane D. Impact of age on human adipose stem cells for bone tissue engineering. Cell Transplant. 2017;26(9):1496–1504.
    1. Strem B, Hocok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005;54(3):132–141.
    1. Buschmann J, Gao S, Harter L, Hemmi S, Welti M, Werner CM, et al. Yield and proliferation rate of adipose-derived stromal cells as a function of age, body mass index and harvest site-increasing the yield by use of adherent and supernatant fractions? Cytotherapy. 2013;15(9):1098–1105.
    1. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005;33(11):1402–1416.
    1. Barlow S, Brooke G, Chatterjee K, Price G, Pelekanos R, Rossetti T, et al. Comparison of human placenta- and bone marrow-derived multipotent mesenchymal stem cells. Stem Cells Dev. 2008;17(6):1095–1107.
    1. Guercio A, Di Marco P, Casella S, Cannella V, Russotto L, Purpari G, et al. Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int. 2012;36(2):189–194.
    1. Harman R, Carlson K, Gaynor J, Gustafson S, Dhupa S, Clement K, et al. A prospective, randomized, masked, and placebo-controlled efficacy study of intraarticular allogeneic adipose stem cells for the treatment of osteoarthritis in dogs. Front Vet Sci. 2016;3:81.
    1. Nixon AJ, Dahlgren LA, Haupt JL, Yeager AE, Ward DL. Effect of adipose-derived nucleated cell fractions on tendon repair in horses with collagenase-induced tendinitis. Am J Vet Res. 2008;69(7):928–937.
    1. Lee RH, Pulin AA, Seo MJ, Kota DJ, Ylostalo J, Larson BL, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009;5(1):54–63.
    1. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–692.
    1. Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol. 2012;3:297.
    1. Spriet M, Hunt GB, Walker NJ, Borjesson DL. Scintigraphic tracking of mesenchymal stem cells after portal, systemic intravenous and splenic administration in healthy beagle dogs. Vet Radiol Ultrasound. 2015;56(3):327–334.
    1. Monsel A, Zhu YG, Gennai S, Hao Q, Liu J, Lee JW. Cell-based therapy for acute organ injury: preclinical evidence and ongoing clinical trials using mesenchymal stem cells. Anesthesiology. 2014;121(5):1099–1121.
    1. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32(3):252–260.
    1. DelaRosa O, Sanchez-Correa B, Morgado S, Ramirez C, del Rio B, Menta R, et al. Human adipose-derived stem cells impair natural killer cell function and exhibit low susceptibility to natural killer-mediated lysis. Stem cells and development. 2012;21(8):1333–1343.
    1. Lee JW, Gupta N, Serikov V, Matthay MA. Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Therapy. 2009;9(10):1259–1270.
    1. Duffy MM, Ritter T, Ceredig R, Griffin MD. Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Therapy. 2011;2(4):34.
    1. Zhou Y, Yamamoto Y, Xiao Z, Ochiya T. The Immunomodulatory functions of mesenchymal stromal/stem cells mediated via paracrine activity. J Clin Med. 2019;8(7):1025.
    1. Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW, et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11(2):150–156.
    1. Prockop DJ, Oh JY. Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation. Mol Therapy. 2012;20(1):14–20.
    1. Prockop DJ. The exciting prospects of new therapies with mesenchymal stromal cells. Cytotherapy. 2017;19(1):1–8.
    1. 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. Lancet Respir Med. 2015;3(1):24–32.
    1. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan. China. Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa248.
    1. Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–3843.
    1. Beyth S, Borovsky Z, Mevorach D, Liebergall M, Gazit Z, Aslan H, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105(5):2214–2219.
    1. Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood. 2005;105(7):2821–2827.
    1. Najar M, Raicevic G, Boufker HI, Fayyad-Kazan H, De Bruyn C, Meuleman N, et al. Adipose-tissue-derived and Wharton’s jelly-derived mesenchymal stromal cells suppress lymphocyte responses by secreting leukemia inhibitory factor. Tissue Eng Part A. 2010;16(11):3537–3546.
    1. Gao L, Zhang Y, Hu B, Liu J, Kong P, Lou S, et al. Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after Hla-Haploidentical Stem-Cell Transplantation. J Clin Oncol. 2016;34(24):2843–2850.
    1. Leyendecker A, Jr, Pinheiro CCG, Amano MT, Bueno DF. The use of human mesenchymal stem cells as therapeutic agents for the in vivo treatment of immune-related diseases: a systematic review. Front Immunol. 2018;9:2056.
    1. Jiang D, Muschhammer J, Qi Y, Kügler A, de Vries JC, Saffarzadeh M, et al. Suppression of neutrophil-mediated tissue damage-a novel skill of mesenchymal stem cells. Stem Cells. 2016;34(9):2393–2406.
    1. Braza F, Dirou S, Forest V, Sauzeau V, Hassoun D, Chesné J, et al. Mesenchymal stem cells induce suppressive macrophages through phagocytosis in a mouse model of asthma. Stem Cells. 2016;34(7):1836–1845.
    1. de Witte SF, Luk F, Sierra Parraga JM, Gargesha M, et al. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. Stem Cells. 2018;36(4):602–615.
    1. Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Buscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut. 2009;58(7):929–939.
    1. Mumaw JL, Schmiedt CW, Breidling S, Sigmund A, Norton NA, Thoreson M, et al. Feline mesenchymal stem cells and supernatant inhibit reactive oxygen species production in cultured feline neutrophils. Res Vet Sci. 2015;103:60–69.
    1. Sônego F, Castanheira FVES, Ferreira RG, Kanashiro A, Leite CAVG, Nascimento DC, et al. Paradoxical roles of the neutrophil in sepsis: protective and deleterious. Front Immunol. 2016;7:155.
    1. Gao P, Yang X, Mungur L, Kampo S, Wen Q. Adipose tissue-derived stem cells attenuate acute lung injury through eNOS and eNOS-derived NO. Int J Mol Med. 2013;31(6):1313–1318.
    1. Gupta K, Hergrueter A, Owen CA. Adipose-derived stem cells weigh in as novel therapeutics for acute lung injury. Stem Cell Res Therapy. 2013;4(1):19.
    1. Liang ZD, Yin XR, Cai DS, Zhou H, Pei L. Autologous transplantation of adipose-derived stromal cells ameliorates ventilator-induced lung injury in rats. J Transl Med. 2013;11(1):179.
    1. Zhang L, Li Q, Liu W, Liu Z, Shen H, Zhao M. Mesenchymal stem cells alleviate acute lung injury and inflammatory responses induced by paraquat poisoning. Med Sci Monit. 2019;25:2623–2632.
    1. Mao YX, Xu JF, Seeley EJ, Tang XD, Xu LL, Zhu YG, et al. Adipose tissue-derived mesenchymal stem cells attenuate pulmonary infection caused by pseudomonas aeruginosa via inhibiting overproduction of prostaglandin E2. Stem Cells. 2015;33(7):2331–2342.
    1. Zheng G, Huang R, Qiu G, Ge M, Wang J, Shu Q, et al. Mesenchymal stromal cell-derived extracellular vesicles: regenerative and immunomodulatory effects and potential applications in sepsis. Cell Tissue Res. 2018;374(1):1–15.
    1. Pedrazza L, Cunha AA, Luft C, Nunes NK, Schimitz F, Gassen RB, 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.
    1. Miao CM, Jiang XW, He K, Li PZ, Liu ZJ, Cao D, et al. Bone marrow stromal cells attenuate LPS-induced mouse acute liver injury via the prostaglandin E 2-dependent repression of the NLRP3 inflammasome in Kupffer cells. Immunol Lett. 2016;179:102–113.
    1. Sung DK, Chang YS, Sung SI, Yoo HS, Ahn SY, Park WS. Antibacterial effect of mesenchymal stem cells against Escherichia coli is mediated by secretion of beta- defensin-2 via toll-like receptor 4 signalling. Cell Microbiol. 2016;18(3):424–436.
    1. Gupta N, Krasnodembskaya A, Kapetanaki M, Mouded M, Tan X, Serikov V, et al. Mesenchymal stem cells enhance survival and bacterial clearance in murine Escherichia coli pneumonia. Thorax. 2012;67(6):533–539.
    1. Mei SH, Haitsma JJ, Dos Santos CC, Deng Y, Lai PF, Slutsky AS, et al. Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis. Am J Respir Crit Care Med. 2010;182(8):1047–1057.
    1. Krasnodembskaya A, Samarani G, Song Y, Zhuo H, Su X, Lee JW, 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(10):L1003–L1013.
    1. Li F, Karlsson H. Antiviral effect of IDO in mouse fibroblast cells during influenza virus infection. Viral Immunol. 2017;30(7):542–544.
    1. Tripathi S, Tecle T, Verma A, Crouch E, White M, Hartshorn KL. The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins. J Gen Virol. 2013;94(Pt 1):40–49.
    1. Mao R, Zhang J, Jiang D, Cai D, Levy JM, Cuconati A, et al. Indoleamine 2,3-dioxygenase mediates the antiviral effect of gamma interferon against hepatitis B virus in human hepatocyte-derived cells. J Virol. 2011;85(2):1048–1057.
    1. Adams O, Besken K, Oberdorfer C, MacKenzie CR, Takikawa O, Daubener W. Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections. J Virol. 2004;78(5):2632–2636.
    1. Moseley TA, Zhu M, Hedrick MH. Adipose-derived stem and progenitor cells as fillers in plastic and reconstructive surgery. Plast Reconstr Surg. 2006;118(3 Suppl):121S–128S.
    1. Obojes K, Andres O, Kim KS, Daubener W, Schneider-Schaulies J. Indoleamine 2,3-dioxygenase mediates cell type-specific anti-measles virus activity of gamma interferon. J Virol. 2005;79(12):7768–7776.
    1. Oliphant S, Lines JL, Hollifield ML, Garvy BA. Regulatory T cells are critical for clearing influenza a virus in neonatal mice. Viral Immunol. 2015;28(10):580–589.
    1. Court AC, Le-Gatt A, Luz-Crawford P, Parra E, Aliaga-Tobar V, Batiz LF, et al. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020;21(2):e48052.
    1. Qian X, Xu C, Fang S, Zhao P, Wang Y, Liu H, et al. Exosomal microRNAs derived from umbilical mesenchymal stem cells inhibit hepatitis C virus infection. Stem cells translational medicine. 2016;5(9):1190–1203.
    1. Alio Del Barrio JL, Chiesa M, Garagorri N, Garcia-Urquia N, Fernandez-Delgado J, Bataille L, et al. Acellular human corneal matrix sheets seeded with human adipose-derived mesenchymal stem cells integrate functionally in an experimental animal model. Exp Eye Res. 2015;132C:91–100.
    1. Hostettler KE, Gazdhar A, Khan P, Savic S, Tamo L, Lardinois D, et al. Multipotent mesenchymal stem cells in lung fibrosis. PLoS ONE. 2017;12(8):e0181946.
    1. Behnke J, Kremer S, Shahzad T, Chao CM, Bottcher-Friebertshauser E, Morty RE, et al. MSC based therapies-new perspectives for the injured lung. J Clin Med. 2020;9(3):682.
    1. Aguilar S, Scotton CJ, McNulty K, Nye E, Stamp G, Laurent G, et al. Bone marrow stem cells expressing keratinocyte growth factor via an inducible lentivirus protects against bleomycin-induced pulmonary fibrosis. PLoS ONE. 2009;4(11):e8013.
    1. Mohammadian M, Sadeghipour HR, Kashani IR, Jahromi GP, Omidi A, Nejad AK, et al. Evaluation of simvastatin and bone marrow-derived mesenchymal stem cell combination therapy on airway remodeling in a mouse asthma model. Lung. 2016;194(5):777–785.
    1. Ni K, Liu M, Zheng J, Wen L, Chen Q, Xiang Z, et al. PD-1/PD-L1 pathway mediates the alleviation of pulmonary fibrosis by human mesenchymal stem cells in humanized mice. Am J Respir Cell Mol Biol. 2018;58(6):684–695.
    1. Gazdhar A, Grad I, Tamo L, Gugger M, Feki A, Geiser T. The secretome of induced pluripotent stem cells reduces lung fibrosis in part by hepatocyte growth factor. Stem Cell Res Therapy. 2014;5(6):123.
    1. Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009;175(1):303–313.
    1. Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20(5):1053–1067.
    1. dos Santos CC, Murthy S, Hu P, Shan Y, Haitsma JJ, Mei SH, et al. Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. Am J Pathol. 2012;181(5):1681–1692.
    1. Zou X, Zhang G, Cheng Z, Yin D, Du T, Ju G, et al. Microvesicles derived from human Wharton’s Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Therapy. 2014;5(2):40.
    1. Jackson MV, Morrison TJ, Doherty DF, McAuley DF, Matthay MA, Kissenpfennig A, 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(8):2210–2223.
    1. Ryter SW, Chen ZH, Kim HP, Choi AM. Autophagy in chronic obstructive pulmonary disease: homeostatic or pathogenic mechanism? Autophagy. 2009;5(2):235–237.
    1. Lee SJ, Smith A, Guo L, Alastalo TP, Li M, Sawada H, et al. Autophagic protein LC3B confers resistance against hypoxia-induced pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(5):649–658.
    1. Li J, Zhou J, Zhang D, Song Y, She J, Bai C. Bone marrow-derived mesenchymal stem cells enhance autophagy via PI3K/AKT signalling to reduce the severity of ischaemia/reperfusion-induced lung injury. J Cell Mol Med. 2015;19(10):2341–2351.
    1. Ghanta S, Tsoyi K, Liu X, Nakahira K, Ith B, Coronata AA, et al. Mesenchymal stromal cells deficient in autophagy proteins are susceptible to oxidative injury and mitochondrial dysfunction. Am J Respir Cell Mol Biol. 2017;56(3):300–309.
    1. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001;163(6):1376–1383.
    1. Huppert LA, Matthay MA. Alveolar fluid clearance in pathologically relevant conditions: in vitro and in vivo models of acute respiratory distress syndrome. Front Immunol. 2017;8:371.
    1. Loy H, Kuok DIT, Hui KPY, Choi MHL, Yuen W, Nicholls JM, et al. Therapeutic implications of human umbilical cord mesenchymal stromal cells in attenuating influenza A(H5N1) virus-associated acute lung injury. J Infect Dis. 2019;219(2):186–196.
    1. Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. 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(38):16357–16362.
    1. Gennai S, Monsel A, Hao Q, Park J, Matthay MA, Lee JW. Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation. Am J Transplant. 2015;15(9):2404–2412.
    1. Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A, et al. Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem cells. 2014;32(1):116–125.
    1. Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ, et al. Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med. 2015;192(3):324–336.
    1. 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.
    1. Xiang B, Chen L, Wang X, Zhao Y, Wang Y, Xiang C. Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of LPS-induced acute lung injury. Int J Mol Sci. 2017;18(4):689.
    1. Chan MC, Kuok DI, Leung CY, Hui KP, Valkenburg SA, Lau EH, et al. Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo. Proc Nat Acad Sci USA. 2016;113(13):3621–3626.
    1. 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(9):e269.
    1. Wu X, Liu Z, Hu L, Gu W, Zhu L. Exosomes derived from endothelial progenitor cells ameliorate acute lung injury by transferring miR-126. Exp Cell Res. 2018;370(1):13–23.
    1. Shah TG, Predescu D, Predescu S. Mesenchymal stem cells-derived extracellular vesicles in acute respiratory distress syndrome: a review of current literature and potential future treatment options. Clin Transl Med. 2019;8(1):25.
    1. McVey M, Tabuchi A, Kuebler WM. Microparticles and acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2012;303(5):L364–L381.
    1. Park J, Kim S, Lim H, Liu A, Hu S, Lee J, 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(1):43–50.
    1. Chen L, Zhang C, Chen L, Wang X, Xiang B, Wu X, et al. Human menstrual blood-derived stem cells ameliorate liver fibrosis in mice by targeting hepatic stellate cells via paracrine mediators. Stem Cells Transl Med. 2017;6(1):272–284.
    1. Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18(5):759–765.
    1. Morrison TJ, Jackson MV, Cunningham EK, Kissenpfennig A, McAuley DF, O’Kane CM, et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196(10):1275–1286.
    1. Tang XD, Shi L, Monsel A, Li XY, Zhu HL, Zhu YG, et al. Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA. Stem Cells. 2017;35(7):1849–1859.
    1. Chang CL, Sung PH, Chen KH, Shao PL, Yang CC, Cheng BC, et al. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am J Transl Res. 2018;10(4):1053–1070.
    1. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24(5):1294–1301.
    1. Izadpanah R, Trygg C, Patel B, Kriedt C, Dufour J, Gimble JM, et al. Biologic properties of mesenchymal stem cells derived from bone marrow and adipose tissue. J Cell Biochem. 2006;99(5):1285–1297.
    1. Ertas G, Ural E, Ural D, Aksoy A, Kozdag G, Gacar G, et al. Comparative analysis of apoptotic resistance of mesenchymal stem cells isolated from human bone marrow and adipose tissue. Sci World J. 2012;2012:105698.
    1. Kim J, Kim HK, Cho HH, Bae YC, Suh KT, Jung JS. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem. 2007;20:867–876.
    1. Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129(1):118–129.
    1. Bochev I, Elmadjian G, Kyurkchiev D, Tzvetanov L, Altankova I, Tivchev P, et al. Mesenchymal stem cells from human bone marrow or adipose tissue differently modulate mitogen-stimulated B-cell immunoglobulin production in vitro. Cell Biol Int. 2008;32(4):384–393.
    1. Ivanova-Todorova E, Bochev I, Mourdjeva M, Dimitrov R, Bukarev D, Kyurkchiev S, et al. Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett. 2009;126(1–2):37–42.
    1. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2013;2(6):455–463.
    1. Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, et al. Bone marrow-derived mesenchymal stem cells in repair of the injured lung. Am J Respir Cell Mol Biol. 2005;33(2):145–152.
    1. Xu J, Woods CR, Mora AL, Joodi R, Brigham KL, Iyer S, et al. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol. 2007;293(1):L131–L141.
    1. Shalaby SM, El-Shal AS, Abd-Allah SH, Selim AO, Selim SA, Gouda ZA, et al. Mesenchymal stromal cell injection protects against oxidative stress in Escherichia coli-induced acute lung injury in mice. Cytotherapy. 2014;16(6):764–775.
    1. Hayes M, Masterson C, Devaney J, Barry F, Elliman S, O’Brien T, et al. Therapeutic efficacy of human mesenchymal stromal cells in the repair of established ventilator-induced lung injury in the rat. Anesthesiology. 2015;122(2):363–373.
    1. 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. Int J Mol Sci. 2018;19(10):2996.
    1. McIntyre LA, Moher D, Fergusson DA, Sullivan KJ, Mei SHJ, Lalu M, et al. Efficacy of mesenchymal stromal cell therapy for acute lung injury in preclinical animal models: a systematic review. PLoS ONE. 2016;11(1):e0147170.
    1. Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol. 2007;179(3):1855–1863.
    1. 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(6):496–501.
    1. 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(1):29.
    1. Maron-Gutierrez TSJ, Asensi KD, et al. Effects of mesenchymal stem cell therapy on the time course of pulmonary remodeling depend on the etiology of lung injury in mice. Crit Care Med. 2013;41(11):e319–e333.
    1. Martínez-González I, Roca O, Masclans JR, Moreno R, Salcedo MT, Baekelandt V, 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(4):552–562.
    1. Shin SKY, Jeong S, et al. The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci. 2013;10:8–18.
    1. Antunes MA, Abreu SC, Cruz FF, Teixeira AC, Lopes-Pacheco M, Bandeira E, et al. Effects of different mesenchymal stromal cell sources and delivery routes in experimental emphysema. Respir Res. 2014;15(1):118.
    1. Cruz FF, Weiss DJ, Rocco PR. Prospects and progress in cell therapy for acute respiratory distress syndrome. Expert Opin Biol Ther. 2016;16(11):1353–1360.
    1. Silva JD, Lopes-Pacheco M, Paz AHR, Cruz FF, Melo EB, de Oliveira MV, et al. Mesenchymal stem cells from bone marrow, adipose tissue, and lung tissue differentially mitigate lung and distal organ damage in experimental acute respiratory distress syndrome. Crit Care Med. 2018;46(2):e132–e140.
    1. Li JW, Wu X. Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells. Eur Rev Med Pharmacol Sci. 2015;19(13):2368–2378.
    1. Luo CJZF, Zhang L, et al. Mesenchymal stem cells ameliorate sepsis associated acute kidney injury in mice. Shock. 2014;41(2):123–129.
    1. Silva JD, de Castro LL, Braga CL, Oliveira GP, Trivelin SA, Barbosa-Junior CM, 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 international. 2019;2019:8262849.
    1. Asmussen S, Ito H, Traber DL, Lee JW, Cox RA, Hawkins HK, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014;69(9):819–825.
    1. Harman R, Hughes M, Shark C, Wrightson C. Results of GLP Safety Study of Intraarticular Stem Cells in the Canine. 2018 North American Veterinary Rewgenerative Medicine Conference; Sacramento, California: NAVRMA; 2018.
    1. Harman R, Rich FR, Schaffer J. Adipose-derived stem cells given intravenously improves epistaxis and objective bronchoscopy scoring in horses with exercise-induced pulmonary hemorrhage. North American Veterinary Regenerative Medicine Conference; 11/17/16; Channel Islands, Florida: NAVRMA; 2016.
    1. Birks EK, Shuler KM, Soma LR, Martin BB, Marconato L, Del Piero F, et al. EIPH: postrace endoscopic evaluation of Standardbreds and Thoroughbreds. Equine Vet J Suppl. 2002;34:375–378.
    1. Derksen F, Williams K, Stack A. Exercise-induced pulmonary hemorrhage in horses: the role of pulmonary veins. Compendium. 2011;33(4):E6.
    1. Hinchcliff KW, Couetil LL, Knight PK, Morley PS, Robinson NE, Sweeney CR, et al. Exercise induced pulmonary hemorrhage in horses: American College of Veterinary Internal Medicine consensus statement. J Vet Intern Med Am Coll Vet Int Med. 2015;29(3):743–758.
    1. Kindig CA, McDonough P, Fenton G, Poole DC, Erickson HH. Efficacy of nasal strip and furosemide in mitigating EIPH in Thoroughbred horses. J Appl Physiol. 2001;91(3):1396–1400.
    1. Manohar M, Goetz TE. Pulmonary vascular pressures of exercising thoroughbred horses with and without endoscopic evidence of EIPH. J Appl Physiol. 1996;81(4):1589–1593.
    1. Sullivan S, Hinchcliff K. Update on exercise-induced pulmonary hemorrhage. Vet Clin North Am Equine Pract. 2015;31(1):187–198.
    1. Sullivan SL, Anderson GA, Morley PS, Hinchcliff KW. Prospective study of the association between exercise-induced pulmonary haemorrhage and long-term performance in Thoroughbred racehorses. Equine Vet J. 2015;47(3):350–357.
    1. Michelotto PV, Jr, Muehlmann LA, Zanatta AL, Bieberbach EW, Kryczyk M, Fernandes LC, et al. Pulmonary inflammation due to exercise-induced pulmonary haemorrhage in Thoroughbred colts during race training. Vet J. 2011;190(2):e3–e6.
    1. Morris ME, Beare JE, Reed RM, Dale JR, LeBlanc AJ, Kaufman CL, et al. Systemically delivered adipose stromal vascular fraction cells disseminate to peripheral artery walls and reduce vasomotor tone through a CD11b+ cell-dependent mechanism. Stem Cells Transl Med. 2015;4(4):369–380.
    1. Rigotti G, Marchi A, Galie M, Baroni G, Benati D, Krampera M, et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstruct Surg. 2007;119(5):1409–1422.
    1. Traktuev DO, Merfeld-Clauss S, Li J, Kolonin M, Arap W, Pasqualini R, et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res. 2008;102(1):77–85.
    1. Usunier B, Benderitter M, Tamarat R, Chapel A. Management of fibrosis: the mesenchymal stromal cells breakthrough. Stem cells international. 2014;2014:340257.
    1. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 2004–2018: is efficacy optimal in a narrow dose range? Stem Cells Transl Med. 2020;9(1):17–27.
    1. Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE. 2012;7(10):e47559.
    1. Peeters CM, Leijs MJ, Reijman M, van Osch GJ, Bos PK. Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review. Osteoarthr Cartil OARS Osteoarthr Res Soc. 2013;21(10):1465–1473.
    1. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281–1290.
    1. Alvaro-Gracia JM, Jover JA, Garcia-Vicuna R, Carreno L, Alonso A, Marsal S, et al. Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis. 2017;76(1):196–202.
    1. Kastrup J, Haack-Sørensen M, Juhl M, Harary Søndergaard R, Follin B, Drozd Lund L, et al. Cryopreserved off-the-shelf allogeneic adipose-derived stromal cells for therapy in patients with ischemic heart disease and heart failure—a safety study. Stem Cells Transl Med. 2017;6(11):1963–1971.
    1. Kuah D, Sivell S, Longworth T, James K, Guermazi A, Cicuttini F, et al. Safety, tolerability and efficacy of intra-articular Progenza in knee osteoarthritis: a randomized double-blind placebo-controlled single ascending dose study. J Transl Med. 2018;16(1):49.
    1. Perlee D, van Vught LA, Scicluna BP, Maag A, Lutter R, Kemper EM, 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.
    1. Freitag J, Bates D, Wickham J, Shah K, Huguenin L, Tenen A, et al. Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med. 2019;14(3):213–230.
    1. Tsai YA, Liu RS, Lirng JF, Yang BH, Chang CH, Wang YC, et al. Treatment of spinocerebellar ataxia with mesenchymal stem cells: a phase I/IIa clinical study. Cell Transplant. 2017;26(3):503–512.
    1. Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, et al. Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol. 2016;3(1):e45–e52.
    1. Kamen DL NP, Wang H, Duke T, Cloud C, Robinson A, et al. CT-04 Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cells (MSCs) in patients with systemic lupus erythematosus: results of an open-label phase I study. Lupus Sci Med. 2018;5.
    1. Schenke-Layland K, Strem BM, Jordan MC, Deemedio MT, Hedrick MH, Roos KP, et al. Adipose tissue-derived cells improve cardiac function following myocardial infarction. J Surg Res. 2009;153(2):217–223.
    1. Zhu Y, Liu T, Song K, Ning R, Ma X, Cui Z. ADSCs differentiated into cardiomyocytes in cardiac microenvironment. Mol Cell Biochem. 2009;324(1–2):117–129.
    1. Bai X, Yan Y, Song YH, Seidensticker M, Rabinovich B, Metzele R, et al. Both cultured and freshly isolated adipose tissue-derived stem cells enhance cardiac function after acute myocardial infarction. Eur Heart J. 2010;31(4):489–501.
    1. White IA, Sanina C, Balkan W, Hare JM. Mesenchymal stem cells in cardiology. Methods Mol Biol. 2016;1416:55–87.
    1. De Francesco F, Romano M, Zarantonello L, Ruffolo C, Neri D, Bassi N, et al. The role of adipose stem cells in inflammatory bowel disease: from biology to novel therapeutic strategies. Cancer Biol Ther. 2016;17(9):889–898.
    1. Gopal SCC. Novel therapy for insulin dependent diabetes mellitus: infusion of in vitro-generated insulin-secreting cells. Clin Exp Med. 2015;15:41–45.
    1. Amer MG, Embaby AS, Karam RA, Amer MG. Role of adipose tissue derived stem cells differentiated into insulin producing cells in the treatment of type I diabetes mellitus. Gene. 2018;654:87–94.
    1. Takahashi H, Sakata N, Yoshimatsu G, Hasegawa S, Kodama S. Regenerative and transplantation medicine: cellular therapy using adipose tissue-derived mesenchymal stromal cells for type 1 diabetes mellitus. J Clin Med. 2019;8(2):249.
    1. Lin KC, Yip HK, Shao PL, Wu SC, Chen KH, Chen YT, et al. Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury. Int J Cardiol. 2016;216:173–185.
    1. Torres Crigna A, Daniele C, Gamez C, Medina Balbuena S, Pastene DO, Nardozi D, et al. Stem/stromal cells for treatment of kidney injuries with focus on preclinical models. Front Med. 2018;5:179.
    1. Song Y, Du H, Dai C, Zhang L, Li S, Hunter DJ, et al. Human adipose-derived mesenchymal stem cells for osteoarthritis: a pilot study with long-term follow-up and repeated injections. Regen Med. 2018;13(3):295–307.
    1. Freitag J, Wickham J, Shah K, Tenen A. Effect of autologous adipose-derived mesenchymal stem cell therapy in the treatment of acromioclavicular joint osteoarthritis. BMJ Case Rep. 2019;12(2):e227865.
    1. Ciuffi S, Zonefrati R, Brandi ML. Adipose stem cells for bone tissue repair. Clin Cases Miner Bone Metab. 2017;14(2):217–226.
    1. Paduano F, Marrelli M, Amantea M, Rengo C, Rengo S, Goldberg M, et al. Adipose tissue as a strategic source of mesenchymal stem cells in bone regeneration: a topical review on the most promising craniomaxillofacial applications. Int J Mol Sci. 2017;18(10):2140.
    1. Kwak KA, Cho HJ, Yang JY, Park YS. Current perspectives regarding stem cell-based therapy for liver cirrhosis. Can J Gastroenterol Hepatol. 2018;2018:4197857.
    1. Bowles AC, Wise RM, Gerstein BY, Thomas RC, Ogelman R, Manayan RC, et al. Adipose stromal vascular fraction attenuates T(H)1 cell-mediated pathology in a model of multiple sclerosis. J Neuroinflamm. 2018;15(1):77.
    1. Fernández O, Izquierdo G, Fernández V, Leyva L, Reyes V, Guerrero M, et al. Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: a triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PLoS ONE. 2018;13(5):e0195891.
    1. Lai K, Zeng K, Zeng F, Wei J, Tan G. Allogeneic adipose-derived stem cells suppress Th17 lymphocytes in patients with active lupus in vitro. Acta Biochim Biophys Sin. 2011;43(10):805–812.
    1. Park MJ, Kwok SK, Lee SH, Kim EK, Park SH, Cho ML. Adipose tissue-derived mesenchymal stem cells induce expansion of interleukin-10-producing regulatory B cells and ameliorate autoimmunity in a murine model of systemic lupus erythematosus. Cell Transplant. 2015;24(11):2367–2377.
    1. Wei S, Xie S, Yang Z, Peng X, Gong L, Zhao K, et al. Allogeneic adipose-derived stem cells suppress mTORC1 pathway in a murine model of systemic lupus erythematosus. Lupus. 2019;28(2):199–209.
    1. Amorin B, Alegretti AP, Valim V, Pezzi A, Laureano AM, da Silva MAL, et al. Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum Cell. 2014;27(4):137–150.
    1. Jurado M, De La Mata C, Ruiz-Garcia A, Lopez-Fernandez E, Espinosa O, Remigia MJ, et al. Adipose tissue-derived mesenchymal stromal cells as part of therapy for chronic graft-versus-host disease: a phase I/II study. Cytotherapy. 2017;19(8):927–936.
    1. Antebi BMA, Batchinsky A. The promise of mesenchymal stem cell therapy for acute respiratory distress syndrome. J Trauma Acute Care Surg. 2018;84(1):183–191.
    1. Toyserkani NM, Jørgensen MG, Tabatabaeifar S, Jensen CH, Sheikh SP, Sørensen JA. Concise review: a safety assessment of adipose-derived cell therapy in clinical trials: a systematic review of reported adverse events. Stem Cells Transl Med. 2017;6(9):1786–1794.
    1. Comella K, Parcero J, Bansal H, Perez J, Lopez J, Agrawal A, et al. Effects of the intramyocardial implantation of stromal vascular fraction in patients with chronic ischemic cardiomyopathy. J Transl Med. 2016;14(1):158.
    1. Perin EC, Sanz-Ruiz R, Sanchez PL, Lasso J, Perez-Cano R, Alonso-Farto JC, et al. Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J. 2014;168(1):88–95.
    1. Henry TD, Pepine CJ, Lambert CR, Traverse JH, Schatz R, Costa M, et al. The Athena trials: autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheter Cardiovasc Interv. 2017;89(2):169–177.
    1. Vanikar AV, Trivedi HL, Kumar A, Gopal SC, Patel HV, Gumber MR, et al. Co-infusion of donor adipose tissue-derived mesenchymal and hematopoietic stem cells helps safe minimization of immunosuppression in renal transplantation—single center experience. Ren Fail. 2014;36(9):1376–1384.
    1. Liang J, Zhang H, Wang D, Feng X, Wang H, Hua B, et al. Allogeneic mesenchymal stem cell transplantation in seven patients with refractory inflammatory bowel disease. Gut. 2012;61(3):468–469.
    1. Tompkins BA, DiFede DL, Khan A, Landin AM, Schulman IH, Pujol MV, et al. Allogeneic mesenchymal stem cells ameliorate aging frailty: a phase II randomized, double-blind, placebo-controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2017;72(11):1513–1522.
    1. Zimmerlin L, Donnenberg AD, Rubin JP, Basse P, Landreneau RJ, Donnenberg VS. Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates. Tissue Eng Part A. 2011;17(1–2):93–106.
    1. Martin-Padura I, Gregato G, Marighetti P, Mancuso P, Calleri A, Corsini C, et al. The white adipose tissue used in lipotransfer procedures is a rich reservoir of CD34 < sup >+</sup > progenitors able to promote cancer progression. Cancer Res. 2012;72(1):325.
    1. Rowan BG, Gimble JM, Sheng M, Anbalagan M, Jones RK, Frazier TP, et al. Human adipose tissue-derived stromal/stem cells promote migration and early metastasis of triple negative breast cancer xenografts. PLoS ONE. 2014;9(2):e89595.
    1. Waked K, Colle J, Doornaert M, Cocquyt V, Blondeel P. Systematic review: the oncological safety of adipose fat transfer after breast cancer surgery. Breast. 2017;31:128–136.
    1. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20(8):1297–1308.
    1. Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, et al. Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2015;21(2):266–274.
    1. Curtis LM, Grkovic L, Mitchell SA, Steinberg SM, Cowen EW, Datiles MB, et al. NIH response criteria measures are associated with important parameters of disease severity in patients with chronic GVHD. Bone Marrow Transplant. 2014;49(12):1513–1520.
    1. Wang L, Zhu CY, Ma DX, Gu ZY, Xu CC, Wang FY, et al. Efficacy and safety of mesenchymal stromal cells for the prophylaxis of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Ann Hematol. 2018;97(10):1941–1950.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. 2020;395(10229):1054–1062.
    1. Levi M, Schultz M, van der Poll T. Disseminated intravascular coagulation in infectious disease. Semin Thromb Hemost. 2010;36(4):367–377.
    1. Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
    1. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res. 2017;149:38–44.
    1. Christy BA, Herzig MC, Montgomery RK, Delavan C, Bynum JA, Reddoch KM, et al. Procoagulant activity of human mesenchymal stem cells. J Trauma Acute Care Surg. 2017;83(1 Suppl 1):S164–S169.
    1. Moll G, Ankrum JA, Kamhieh-Milz J, Bieback K, Ringden O, Volk HD, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019;25(2):149–163.
    1. Moll G, Rasmusson-Duprez I, von Bahr L, Connolly-Andersen AM, Elgue G, Funke L, et al. Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells. 2012;30(7):1565–1574.
    1. George MJ, Prabhakara K, Toledano-Furman NE, Wang YW, Gill BS, Wade CE, et al. Clinical cellular therapeutics accelerate clot formation. Stem Cells Transl Med. 2018;7(10):731–739.
    1. Perlee D, de Vos AF, Scicluna BP, Maag A, Mancheno P, de la Rosa O, 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 Therapy. 2019;10(1):286.
    1. Moll G, Ignatowicz L, Catar R, Luecht C, Sadeghi B, Hamad O, et al. Different procoagulant activity of therapeutic mesenchymal stromal cells derived from bone marrow and placental decidua. Stem Cells and Dev. 2015;24(19):2269–2279.
    1. Liao L, Shi B, Chang H, Su X, Zhang L, Bi C, et al. Heparin improves BMSC cell therapy: anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy. Theranostics. 2017;7(1):106–116.
    1. Obi AT, Tignanelli CJ, Jacobs BN, Arya S, Park PK, Wakefield TW, et al. Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients. J Vasc Surg Venous Lymph Disord. 2019;7(3):317–324.
    1. 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. Lancet Respir Med. 2019;7(2):154–162.
    1. Zheng G, Huang L, Tong H, Shu Q, Hu Y, Ge M, 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(1):39.
    1. Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalen M, et al. In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome. Stem Cells Transl Med. 2015;4(10):1199–1213.
    1. Agrawal A, Matthay MA, Kangelaris KN, Stein J, Chu JC, Imp BM, et al. Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients. Am J Respir Crit Care Med. 2013;187(7):736–742.
    1. Calfee CS, Gallagher D, Abbott J, Thompson BT, Matthay MA. Plasma angiopoietin-2 in clinical acute lung injury: prognostic and pathogenetic significance. Crit Care Med. 2012;40(6):1731–1737.
    1. Zinter MS, Spicer A, Orwoll BO, Alkhouli M, Dvorak CC, Calfee CS, et al. Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality. Am J Physiol Lung Cell Mol Physiol. 2016;310(3):L224–L231.
    1. Gutbier BNA, Reppe K, et al. Prognostic and pathogenic role of angiopoietin-1 and -2 in pneumonia. Am J Respir Crit Care Med. 2018;198:220–231.
    1. Bhandari V, Choo-Wing R, Lee CG, Zhu Z, Nedrelow JH, Chupp GL, et al. Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med. 2006;12(11):1286–1293.
    1. Parikh SM. Angiopoietins and Tie2 in vascular inflammation. Curr Opin Hematol. 2017;24(5):432–438.
    1. Athersys. Athersys Provides Update on One-Year ARDS Study Data 2020. .
    1. Liu Y, Sun W, Li J, Chen L, Wang Y, Zhang L, et al. Clinical features and progression of acute respiratory distress syndrome in coronavirus disease 2019. medRxiv. 2020 doi: 10.1101/2020.02.17.20024166.
    1. Liang B CJ, Li T, Wu H, Yang W, Li Y, Li J, Yu C, Nie F, Ma Z, Yang M, Nie P, Gao Y, Qian C, Hu M. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells 2020. .
    1. Shetty AK. Mesenchymal stem cell infusion shows promise for combating coronavirus (COVID-19)-induced pneumonia. Aging and disease. 2020;11(2):462.
    1. Pluristem. Pluristem Reports Preliminary Data from its COVID-19 Compassionate Use Program, Treating Seven Patients with Acute Respiratory Failure 2020 [Clinical study results]. . Accessed 7 Apr 2020.
    1. Sami T. Mesoblast reports 83% survival in ventilator-dependent COVID-19 patients following stem cell therapy: BioWorld; 2020 [Preliminary clinical trial results]. . Accessed 24 Apr 2020.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera