Menstrual Blood-Derived Mesenchymal Stem Cell Therapy for Severe
COVID-19 Patients

Fezzeh      Heidari; Reza      Heidari; Mehrdad   Nasrollahzadeh   Sabet; Amir   Ali   Hamidieh; Zohreh      Saltanatpour

doi:10.2174/1574888X18666230417085117

Abstract

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), was declared a global pandemic in March 2020 and resulted in more than 6 million deaths worldwide to date. Although several vaccines were produced against COVID-19 and many therapeutic protocols were developed for the management of this respiratory infection, COVID-19 pandemic has still remained an unresolved problem with the emergence of new variants of SARS-CoV-2, especially vaccine-resistant variants. Probably, end of the COVID-19 needs effective and certain treatments which were undiscovered to date. According to immunomodulatory and regenerative properties, mesenchymal stem cells (MSCs) have been considered a therapeutic approach to suppressing cytokine storm caused by SARS-CoV-2 and the treatmet of severe COVID-19. Following intravenous (IV) infusion of MSCs, cells entrap in the lung, guard alveolar epithelial cells, suppress pulmonary fibrosis and improve lung dysfunction. The human menstrual blood-derived stem cells (hMenSCs) as a novel source of MSCs are collected by noninvasive, painless, and easy way without ethical issues. MenScs are an abundant and cheap source with a high proliferation rate and differentiation ability into multiple cell lineages. Regarding immunomodulatory and anti-inflammatory properties, regenerative ability and low immunogenicity, these cells exhibit great potential in the treatment of various diseases. Some clinical trial studies have begun using MenSCs to treat severe COVID-19. According to these trials, MenSC therapy showed promising and encouraging results in treating severe COVID-19. We reviewed published clinical trials and summarized the effects of MenSC therapy on severe COVID-19 with a focus on clinical and laboratory data, immune and inflammatory factors and concluded the advantages and possible risks of this procedure.

« Previous Next »

Graphical Abstract

[1]
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet  2020; 395(10223): 497-506.
 [http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]

[2]
Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. N Engl J Med  2020; 382(13): 1199-207.
 [http://dx.doi.org/10.1056/NEJMoa2001316] [PMID: 31995857]

[3]
Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: Retrospective case series. BMJ  2020; 368: m606.
 [http://dx.doi.org/10.1136/bmj.m606] [PMID: 32075786]

[4]
Golchin A, Seyedjafari E, Ardeshirylajimi A. Mesenchymal stem cell therapy for COVID-19: Present or future. Stem Cell Rev Rep  2020; 16(3): 427-33.
 [http://dx.doi.org/10.1007/s12015-020-09973-w] [PMID: 32281052]

[5]
Fontanet A, Autran B, Lina B, Kieny MP, Karim SSA, Sridhar D. SARS-CoV-2 variants and ending the COVID-19 pandemic. Lancet  2021; 397(10278): 952-4.
 [http://dx.doi.org/10.1016/S0140-6736(21)00370-6] [PMID: 33581803]

[6]
Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B. 1.617. 2 (Delta) variant. N Engl J Med  2021; 385(7): 585-94.
 [http://dx.doi.org/10.1056/NEJMoa2108891] [PMID: 34289274]

[7]
Mascola JR, Graham BS, Fauci AS. SARS-CoV-2 viral variants-Tackling a moving target. JAMA  2021; 325(13): 1261-2.
 [http://dx.doi.org/10.1001/jama.2021.2088] [PMID: 33571363]

[8]
Durand N, Mallea J, Zubair AC. Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure. NPJ Regen Med  2020; 5(1): 17.
 [http://dx.doi.org/10.1038/s41536-020-00105-z] [PMID: 33580031]

[9]
Gao F, Chiu SM, Motan D A L, et al. Mesenchymal stem cells and immunomodulation: Current status and future prospects. Cell Death Dis  2016; 7(1): e2062.
 [http://dx.doi.org/10.1038/cddis.2015.327] [PMID: 26794657]

[10]
Gebler A, Zabel O, Seliger B. The immunomodulatory capacity of mesenchymal stem cells. Trends Mol Med  2012; 18(2): 128-34.
 [http://dx.doi.org/10.1016/j.molmed.2011.10.004] [PMID: 22118960]

[11]
Shi M, Liu Z, Wang Y, et al. A pilot study of mesenchymal stem cell therapy for acute liver allograft rejection. Stem Cells Transl Med  2017; 6(12): 2053-61.
 [http://dx.doi.org/10.1002/sctm.17-0134] [PMID: 29178564]

[12]
Chen L, Qu J, Cheng T, Chen X, Xiang C. Menstrual blood-derived stem cells: Toward therapeutic mechanisms, novel strategies, and future perspectives in the treatment of diseases. Stem Cell Res Ther  2019; 10(1): 406.
 [http://dx.doi.org/10.1186/s13287-019-1503-7] [PMID: 31864423]

[13]
Samsonraj RM, Raghunath M, Nurcombe V, Hui JH, van Wijnen AJ, Cool SM. Concise review: Multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med  2017; 6(12): 2173-85.
 [http://dx.doi.org/10.1002/sctm.17-0129] [PMID: 29076267]

[14]
Golchin A, Farahany TZ, Khojasteh A, Soleimanifar F, Ardeshirylajimi A. The clinical trials of mesenchymal stem cell therapy in skin diseases: An update and concise review. Curr Stem Cell Res Ther  2019; 14(1): 22-33.
 [http://dx.doi.org/10.2174/1574888X13666180913123424] [PMID: 30210006]

[15]
Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2- Mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis  2020; 11(2): 216-28.
 [http://dx.doi.org/10.14336/AD.2020.0228] [PMID: 32257537]

[16]
Bing L, Junhui C, Tao Li, Haiying Wu, Wenjie Y, Yanjiao Li, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells. Medicine  2020; 99(31): e21429.
 [http://dx.doi.org/10.12074/202002.00084]

[17]
Sengupta V, Sengupta S, Lazo A, Woods P, Nolan A, Bremer N. Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19. Stem Cells Dev  2020; 29(12): 747-54.
 [http://dx.doi.org/10.1089/scd.2020.0080] [PMID: 32380908]

[18]
Galea C, Riva N, Calleja-Agius J. Non-gynaecological applications of menstrual-derived stem cells: A systematic review. Avicenna J Med Biotechnol  2022; 14(1): 10-29.
 [http://dx.doi.org/10.18502/ajmb.v14i1.8166] [PMID: 35509365]

[19]
Chen S, Dong C, Zhang J, Tang B, Xi Z, Cai F, et al. Human menstrual blood-derived stem cells protect H9c2 cells against hydrogen peroxide-associated apoptosis. In Vitro Cell Dev Biol Anim  2019; 55(2): 104-12.

[20]
Azedi F, Kazemnejad S, Zarnani AH, Soleimani M, Shojaei A, Arasteh S. Comparative capability of menstrual blood versus bone marrow derived stem cells in neural differentiation. Mol Biol Rep  2017; 44(1): 169-82.
 [http://dx.doi.org/10.1007/s11033-016-4095-7] [PMID: 27981446]

[21]
Khanjani S, Khanmohammadi M, Zarnani AH, et al. Comparative evaluation of differentiation potential of menstrual blood- versus bone marrow-derived stem cells into hepatocyte-like cells. PLoS One  2014; 9(2): e86075.
 [http://dx.doi.org/10.1371/journal.pone.0086075] [PMID: 24505254]

[22]
Skliutė G, Baušytė R, Borutinskaitė V, et al. Menstrual bloodderived endometrial stem cells’ impact for the treatment perspective of female infertility. Int J Mol Sci  2021; 22(13): 6774.
 [http://dx.doi.org/10.3390/ijms22136774] [PMID: 34202508]

[23]
Chang QY, Zhang SW, Li PP, Yuan ZW, Tan JC. Safety of menstrual blood-derived stromal cell transplantation in treatment of intrauterine adhesion. World J Stem Cells  2020; 12(5): 368-80.
 [http://dx.doi.org/10.4252/wjsc.v12.i5.368] [PMID: 32547685]

[24]
Chen L, Qu J, Xiang C. The multi-functional roles of menstrual blood-derived stem cells in regenerative medicine. Stem Cell Res Ther  2019; 10(1): 1.
 [http://dx.doi.org/10.1186/s13287-018-1105-9] [PMID: 30606242]

[25]
Tang L, Jiang Y, Zhu M, et al. Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19. Front Med  2020; 14(5): 664-73.
 [http://dx.doi.org/10.1007/s11684-020-0810-9] [PMID: 32761491]

[26]
Xu X, Jiang W, Chen L, et al. Evaluation of the safety and efficacy of using human menstrual blood‐derived mesenchymal stromal cells in treating severe and critically ill COVID‐19 patients: An exploratory clinical trial. Clin Transl Med  2021; 11(2): e297.
 [http://dx.doi.org/10.1002/ctm2.297] [PMID: 33634996]

[27]
Lu J, Xie ZY, Zhu DH, Li LJ. Human menstrual blood-derived stem cells as immunoregulatory therapy in COVID-19: A case report and review of the literature. World J Clin Cases  2021; 9(7): 1705-13.
 [http://dx.doi.org/10.12998/wjcc.v9.i7.1705] [PMID: 33728315]

[28]
Fathi-Kazerooni M, Fattah-Ghazi S, Darzi M, et al. Safety and efficacy study of allogeneic human menstrual blood stromal cells secretome to treat severe COVID-19 patients: Clinical trial phase I & II. Stem Cell Res Ther  2022; 13(1): 96.
 [http://dx.doi.org/10.1186/s13287-022-02771-w] [PMID: 35255966]

[29]
Cao AJW, Jeyaraj D, Liu H. Co-administration of menstrual blood-derived stem cells and remdesivir for the treatment of severe coronavirus disease 2019 (COVID-19) induced pneumonia: A research protocol. URNCST J  2022; 6: 1-12.
 [http://dx.doi.org/10.26685/urncst.319]

[30]
Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature  2020; 581(7809): 465-9.
 [http://dx.doi.org/10.1038/s41586-020-2196-x] [PMID: 32235945]

[31]
Drosten C, Günther S, Preiser W, et al. Identification of a novel coronavirus in patients with severe acute respiratory syndrome. N Engl J Med  2003; 348(20): 1967-76.
 [http://dx.doi.org/10.1056/NEJMoa030747] [PMID: 12690091]

[32]
Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus ADME, Fouchier RAM. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med  2012; 367(19): 1814-20.
 [http://dx.doi.org/10.1056/NEJMoa1211721] [PMID: 23075143]

[33]
Gorbalenya AE, Baker SC, Baric RS, et al. The species Severe acute respiratory syndrome-related coronavirus: Classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol  2020; 5(4): 536-44.
 [http://dx.doi.org/10.1038/s41564-020-0695-z] [PMID: 32123347]

[34]
Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature  2020; 583(7816): 459-68.
 [http://dx.doi.org/10.1038/s41586-020-2286-9] [PMID: 32353859]

[35]
Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature  2020; 579(7798): 270-3.
 [http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]

[36]
Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. Cell  2020; 181(2): 271-280.e8.
 [http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID: 32142651]

[37]
Zaki MM, Lesha E, Said K, et al. Cell therapy strategies for COVID-19: Current approaches and potential applications. Sci Adv  2021; 7(33): eabg5995.
 [http://dx.doi.org/10.1126/sciadv.abg5995] [PMID: 34380619]

[38]
Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol  2004; 203(2): 631-7.
 [http://dx.doi.org/10.1002/path.1570] [PMID: 15141377]

[39]
Trougakos IP, Stamatelopoulos K, Terpos E, et al. Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications. J Biomed Sci  2021; 28(1): 9.
 [http://dx.doi.org/10.1186/s12929-020-00703-5] [PMID: 33435929]

[40]
Schoeman D, Fielding BC. Coronavirus envelope protein: Current knowledge. Virol J  2019; 16(1): 69.
 [http://dx.doi.org/10.1186/s12985-019-1182-0] [PMID: 31133031]

[41]
V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat Rev Microbiol  2021; 19(3): 155-70.
 [http://dx.doi.org/10.1038/s41579-020-00468-6] [PMID: 33116300]

[42]
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol  2008; 8(9): 726-36.
 [http://dx.doi.org/10.1038/nri2395] [PMID: 19172693]

[43]
Novello S, Debouche A, Philippe M, Naudet F, Jeanne S. Clinical application ofmesenchymal stem cells in periodontalre generation: A systematic review and meta-analysis. J Periodontal Res  2020; 55(1): 1-12.

[44]
Zhao K, Liu Q. The clinical application of mesenchymal stromal cells in hematopoietic stem cell transplantation. J Hematol Oncol  2016; 9(1): 46.
 [http://dx.doi.org/10.1186/s13045-016-0276-z]

[45]
Chen J, Hu C, Chen L, et al. Clinical study of Mesenchymal stem cell treatment for acute respiratory distress syndrome induced by Epidemic Influenza A (H7N9) infection: A hint for COVID-19 treatment. Engineering  2020; 6(10): 1153-61.
 [http://dx.doi.org/10.1016/j.eng.2020.02.006] [PMID: 32292627]

[46]
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(1): 39.
 [http://dx.doi.org/10.1186/1465-9921-15-39] [PMID: 24708472]

[47]
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(2): 154-62.
 [http://dx.doi.org/10.1016/S2213-2600(18)30418-1] [PMID: 30455077]

[48]
Yip HK, Fang WF, Li YC, et al. Human umbilical cord-derived mesenchymal stem cells for acute respiratory distress syndrome. Crit Care Med  2020; 48(5): e391-9.
 [http://dx.doi.org/10.1097/CCM.0000000000004285] [PMID: 32187077]

[49]
Simonson OE, Mougiakakos D, Heldring N, 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): 1199-213.
 [http://dx.doi.org/10.5966/sctm.2015-0021] [PMID: 26285659]

[50]
Kong Y, Shao Y, Ren C, Yang G. Endometrial stem/progenitor cells and their roles in immunity, clinical application, and endometriosis. Stem Cell Res Ther  2021; 12(1): 474.
 [http://dx.doi.org/10.1186/s13287-021-02526-z] [PMID: 34425902]

[51]
Marinaro F, Gómez-Serrano M, Jorge I, et al. Unraveling the molecular signature of extracellular vesicles from endometrial-derived mesenchymal stem cells: Potential modulatory effects and therapeutic applications. Front Bioeng Biotechnol  2019; 7: 431.
 [http://dx.doi.org/10.3389/fbioe.2019.00431] [PMID: 31921832]

[52]
Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Exp Mol Med  2013; 45(11): e54.
 [http://dx.doi.org/10.1038/emm.2013.94] [PMID: 24232253]

[53]
Pittenger MF, Discher DE, Péault BM, Phinney DG, Hare JM, Caplan AI. Mesenchymal stem cell perspective: Cell biology to clinical progress. NPJ Regen Med  2019; 4(1): 22.
 [http://dx.doi.org/10.1038/s41536-019-0083-6] [PMID: 31815001]

[54]
Chow L, Johnson V, Impastato R, Coy J, Strumpf A, Dow S. Antibacterial activity of human mesenchymal stem cells mediated directly by constitutively secreted factors and indirectly by activation of innate immune effector cells. Stem Cells Transl Med  2020; 9(2): 235-49.
 [http://dx.doi.org/10.1002/sctm.19-0092] [PMID: 31702119]

[55]
Wang S, Guo L, Ge J, et al. Excess integrins cause lung entrapment of mesenchymal stem cells. Stem Cells  2015; 33(11): 3315-26.
 [http://dx.doi.org/10.1002/stem.2087] [PMID: 26148841]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1574888X18666230417085117	Print ISSN 1574-888X
Publisher Name Bentham Science Publisher	Online ISSN 2212-3946

Current Stem Cell Research & Therapy

Menstrual Blood-Derived Mesenchymal Stem Cell Therapy for Severe COVID-19 Patients

Abstract Play Pause

Graphical Abstract

Related Books

Abstract