The Systematic Effect of Mesenchymal Stem Cell Therapy in Critical COVID-19 Patients: A Prospective Double Controlled Trial

G Adas, Z Cukurova, K Kart Yasar, R Yilmaz, N Isiksacan, P Kasapoglu, Z Yesilbag, I D Koyuncu, E Karaoz, G Adas, Z Cukurova, K Kart Yasar, R Yilmaz, N Isiksacan, P Kasapoglu, Z Yesilbag, I D Koyuncu, E Karaoz

Abstract

The aim of this clinical trial was to control the cytokine storm by administering mesenchymal stem cells (MSCs) to critically-ill COVID-19 patients, to evaluate the healing effect, and to systematically investigate how the treatment works. Patients with moderate and critical COVID-19 clinical manifestations were separated as Group 1 (moderate cases, n = 10, treated conventionally), Group 2 (critical cases, n = 10, treated conventionally), and Group 3 (critical cases, n = 10, treated conventionally plus MSCs transplantation therapy of three consecutive doses on treatment days 0, 3, and 6, (as 3 × 106 cells/kg, intravenously). The treatment mechanism of action was investigated with evaluation markers of the cytokine storm, via biochemical parameters, levels of proinflammatory and anti-inflammatory cytokines, analyses of tissue regeneration via the levels of growth factors, apoptosis markers, chemokines, matrix metalloproteinases, and granzyme-B, and by the assessment of the immunomodulatory effects via total oxidant/antioxidant status markers and the levels of lymphocyte subsets. In the assessment of the overall mortality rates of all the cases, six patients in Group-2 and three patients in Group-3 died, and there was no loss in Group-1. Proinflammatory cytokines IFNγ, IL-6, IL-17A, IL-2, IL-12, anti-inflammatory cytokines IL-10, IL-13, IL-1ra, and growth factors TGF-β, VEGF, KGF, and NGF levels were found to be significant in Group-3. When Group-2 and Group-3 were compared, serum ferritin, fibrinogen and CRP levels in Group-3 had significantly decreased. CD45 +, CD3 +, CD4 +, CD8 +, CD19 +, HLA-DR +, and CD16 + / CD56 + levels were evaluated. In the statistical comparison of the groups, significance was only determined in respect of neutrophils. The results demonstrated the positive systematic and cellular effects of MSCs application on critically ill COVID-19 patients in a versatile way. This effect plays an important role in curing and reducing mortality in critically ill patients.

Keywords: COVID-19; cytokines; growth factors; mesenchymal stem cell.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
The trial design consisting of three arms. (R: randomization).
Figure 2.
Figure 2.
The changes in the inflammatory pathway indicators. *p< 0.05; **p < 0.005.
Figure 3.
Figure 3.
The changes in the white blood cells (WBC), lymphocytes (Lym), and neutrophils (Neu). *p < 0.05; **p< 0.005; ***p < 0.001.

References

    1. Li CY, Bai ZW, Hashikawa T. The neuro invasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol. 2020;92(6):552–555.
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, et al. Clinical characteristic of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–1069.
    1. Han J, Li Y, Li Y. Strategies to enhance Mesenchymal stem cell-based therapies for acute respiratory distress syndrome. Stem Cells Int. 2019;1–12.
    1. Atluri S, Manchikanti L, Hirsch AJ. Expanded umblical cord mesenchymal stem cells (UC-MSCs) as a therapeutic strategy in managing critically ill COVID-19 patients: the case for compassionate use. Pain Physician. 2020;23(2):E71–E83.
    1. Wu Z, Mcgoogan JM. Characteristic of and important lessons from the coronavirus disease 2019 (C0VID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese center for disease control and prevention. JAMA. 2020;323(13):1239–1249.
    1. Li H, Shen S, Fu H, Wang Z, Li X, Sui X, Yuan M, Liu S, Wang G, Guo Q. Immunomodulatory functions of mesenchymal stem cells in tissue engineering. Stem Cells Int. 2019;2019:9671206.
    1. Lee JW, Fang X, Krasnodembskaya A, Howard JP, Matthaya M. Concise review: mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells. 2011;29(6);913–919.
    1. Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty ER, Bellusci S, Ehrhardt H. MSC based therapies-new perspectives for the injured lung. J Clin Med. 2020;9(3);682.
    1. Peng F, Tu L, Yang Y, Hu P, Wang R, Hu Q, Cao F, Jiang T, Sun J, Xu G, Chang C. Management and treatment of COVID-19: the Chinese experience 2019. Can J Cardiol. 2020;36(6);915–930.
    1. Poston JT, Patel BK, Davis AM. Management of critically ill adults with COVID-19. JAMA. 2020;323(18):1839–1841. doi:10.1001/jama.2020.4914
    1. Kabatas S, Civelek E, Inci C, Yalcınkaya EY, Gunel G, Kır G, Albayrak E, Ozturk E, Adas G, Karaoz E. Wharton’s jelly-derived mesenchymal stem cell transplantation in a patient with hypoxic-ischemic encephalopathy: a pilot study. Cell Transplant. 2018;27(10):1425–1433.
    1. Channappanavar R, Perlman S. Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology. Semin Immunpathol. 2017;39(5):529–539.
    1. Davidson S, Maini MK, Wack A. Disease-promoting effects of type 1 interferons in viral, bacterial, and coinfections. J Interf Cytokine Res. 2015:35(4):252–264.
    1. Koyuncu ID, Darici H, Karaoz E. Stem cell-based therapy option in COVID-19: is it really promising? Aging Dis. 2020;11(4):1–17.
    1. Xia S, Zhou C, Kalionis B, Shuang X, GE H, Gao W. Combined antioxidant, anti-inflammaging and mesenchymal stem cell treatment: a possible therapeutic direction in elderly patients with chronic obstructive pulmonary disease. Aging Dis. 2020;11(1):129–140.
    1. Ahmed MS, Morsi M, Ghoneim IN, Abdel-Daim M, Badri EN. Mesenchymal stromal cell therapy for pancreatitis: a systemic review. Oxidat Med Cellu Longev. 2018:1–14.
    1. Zhand S, Jazi MS, Mohammadi S, Tarighati Rasekhi R, Rostamian G, Kalani MR, Aida Rostamian A, George J, Douglas MW. COVID-19: The immune responses and Clinical therapy candidates. Int J Mol Sci. 2020;21(15):5559.
    1. Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: a meta analysis. J Med Virol. 2021;93(1):35–37.
    1. Chenliang G, Yan H. In silico prediction of molecular targets of astragaloside iv for alleviation of COVID-19 hyperinflammation by systems network pharmacology and bioinformatic gene expression analysis. Front Pharmacol. 2020;11:1–11.
    1. Liu M, Guo S, Hibbert MJ, Jain V, Singh N, Wilson ON, Stiles KJ. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 2011;22(3):121–130.
    1. Oliviero A, Castro Coperchini F, Chiovato L, Rotondi M. COVID-19 pulmonary and olfactory dysfunctions: is the chemokine CXCL10 the common denominator? The Neuroscientist. 2021;27(3):214–221.
    1. Sekhon SB. Matrix metalloproteinases – an overview. Res Rep Biol. 2010;1:1–20.
    1. Esquivel D, Mishra R, Soni P, Seetharaman R, Mahmood A, Srivastava1 A. Stem cells therapy as a possible therapeutic option in treating COVID-19 patients. Stem Cell Rev Rep. 2020;17(1):144–152.
    1. Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Shan G, Meng F, Du D, Wang S, Fan F, et al. Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis. 2020;11(2);216–228.
    1. Panganiban AM, Day RM. Hepatocyte growth factor in lung repair and pulmonary fibrosis. Acta Pharmacol Sin. 2011;32(1):12–20.
    1. Xiao K, Hou F, Huang X, Li B, Qian RZ, Xiao XL. Mesenchymal stem cells: current clinical progress in ARDS and COVID-19. Stem Cell Res Ther. 2020;11(1);305.
    1. Kumar A, Ghosh B. Emerging treatment options of regenerative medicine in severe corona virüs/COVID-19 infections. Int J of Stem cells. 2020;13(3):305–311.
    1. Thej C, Ramadasse B, Walvekar A, Majumdar SA, Balasubramanian S. Development of a surrogate potency assay to determine the angiogenic activity of Stempeucel, a pooled, ex-vivo expanded, allogeneic human bone marrow mesenchymal stromal cell product. Stem Cell Res Ther. 2017;8(1):47.
    1. Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, Wang S, Zhang C, Yuan X, Xu Z, Huang L, et al. Treatment with human umbilical cord-derived mesenchymal stem cells for COVID-19 patients with lung damage: a randomised, double-blind, placebo-controlled phase 2 trial. medRxiv preprint. 2020.10.15.20213553; doi: 10.1101/2020.10.15.20213553
    1. Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130(5): 2620–2625.
    1. Liang B, Chen J, Li T, Wu H, Yang W, Li Y, Li J, Yu C, Nie F, Ma Z, Yang M, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: a case report. Medicine. 2020;99(31):e21429.
    1. Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, Chen L, Li M, Liu Y, Wang G, Yuan Z, et al. Reduction and functional exhaustion of t cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol. 2020;11:827.
    1. Choudlery SM, Harris TD. Stem cell therapy for COVID-19: possibilities and challenges. Cell Biol Int. 2020;44(11):2182–2191.
    1. Fischer MU, Harting TM, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS, Jr. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 2009;18(5):683–692.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa