Bioactive Lipids as Mediators of the Beneficial Action(s) of Mesenchymal Stem Cells in COVID-19
Das Undurti N1,2,*
1UND Life Sciences, Battle Ground, WA 98604, USA 2BioScience Research Centre and Department of Medicine, Gayatri Vidya Parishad Medical College and Hospital, Visakhapatnam-530048, India.
It is proposed that the beneficial action of mesenchymal stem cells (MSCs) in COVID-19 and other inflammatory diseases could be attributed to their ability to secrete bioactive lipids (BALs) such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) and other similar BALs. This implies that MSCs that have limited or low capacity to secrete BALs may be unable to bring about their beneficial actions. This proposal implies that pretreatment of MSCs with BALs enhance their physiological action or improve their (MSCs) anti-inflammatory and disease resolution capacity to a significant degree. Thus, the beneficial action of MSCs reported in the management of COVID-19 could be attributed to their ability to secrete BALs, especially PGE2 and LXA4. Since PGE2, LXA4 and their precursors AA (arachidonic acid), dihomo-gamma-linolenic acid (DGLA) and gamma-linolenic acid (GLA) inhibit the production of pro-inflammatory IL-6 and TNF-α, they could be employed to treat cytokine storm seen in COVID-19, immune check point inhibitory (ICI) therapy, sepsis and ARDS (acute respiratory disease). This is further supported by the observation that GLA, DGLA and AA inactivate enveloped viruses including COVID-19. Thus, infusions of appropriate amounts of GLA, DGLA, AA, PGE2 and LXA4 are of significant therapeutic benefit in COVID-19, ICI therapy and other inflammatory conditions including but not limited to sepsis. AA is the precursor of both PGE2 and LXA4 suggesting that AA is most suited for such preventive and therapeutic approach.
Das Undurti N. Bioactive Lipids as Mediators of the Beneficial Action(s) of Mesenchymal Stem Cells in COVID-19[J]. Aging and disease,
2020, 11(4): 746-755.
Figure 1. Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who recovers. AA is released from the cell membrane in two phases, first phase is used for PGE2 synthesis, whereas the second phase is meant for LXA4 synthesis. Once PGE2 concentration reaches its peak, LXA4 synthesis is triggered that induces resolution of inflammation. AA release is triggered by SARS-CoV-2 and other infections.
Figure 2. Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who succumbs to the disease. Note the absence of biphasic nature of AA release and failure of PGE2 to reach its peak and as a result deficiency in LXA4 synthesis occurs that results in failure of resolution of inflammation (compare with Fig 1). DGLA, EPA and DHA (not shown in the figure) may have actions/functions like AA.
Figure 3. Scheme showing possible role of MSCs and bioactive lipids in COVID-19. Dietary LA and ALA are converted to AA and EPA and DHA by desaturases. Viruses block the activities of desaturases. PGE2 and LTs derived from AA/EPA/DHA facilitate M1 generation and enhance inflammation. Anti-inflammatory PGE1/PGE2, lipoxins, resolvins, protectins and maresins derived from DGLA, AA, EPA and DHA facilitate M2 generation and suppress inflammation. PLA2 activated by SARS-CoV-2 and other viruses induce the release of DGLA/AA/EPA/DHA that inactivate enveloped viruses by themselves and through their products and regulate inflammatory process. MSCs and other stem cells contain DGLA/AA/EPA/DHA and release PGE2 and LXA4 and other bioactive lipids to resolve inflammation. DGLA/AA/EPA/DHA by their ability to alter cell membrane composition can regulate ACE2 expression. ACE2 is needed for SARS-CoV-2 entry into the cells.
[1]
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q (2020). Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science, in press.
[2]
Das UN (2020). Can Bioactive Lipids Inactivate Coronavirus (COVID-19)? Arch Med Res, pii: S0188-4409(20)30292-7.
[3]
Das UN (2020). Bioactive lipids and Coronavirus (COVID-19)-further discussion. Arch Med Res, in press.
[4]
Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, Shan G, et al. (2020). Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia. Aging Dis, 11: 216-228.
[5]
Wang Y, Chen X, Cao W, Shi Y (2014). Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol, 15: 1009-1016.
[6]
Abdelmawgoud H, Saleh A (2018). Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model. Adv Clin Exp Med, 27: 873-880.
[7]
Zhang Z, Huang S, Wu S, Qi J, et al. (2019). Clearance of apoptotic cells by mesenchymal stem cells contributes to immunosuppression via PGE2. EBioMedicine, 45: 341-350.
[8]
Holopainen M, Colas RA, Valkonen S, Tigistu-Sahle F, et al. (2019). Polyunsaturated fatty acids modify the extracellular vesicle membranes and increase the production of proresolving lipid mediators of human mesenchymal stromal cells. Biochim Biophys Acta Mol Cell Biol Lipids, 1864: 1350-1362.
[9]
Hyvärinen K, Holopainen M, Skirdenko V, Ruhanen H, Lehenkari P, Korhonen M, Käkelä R, Laitinen S, Kerkelä E (2018). Mesenchymal Stromal Cells and Their Extracellular Vesicles Enhance the Anti-Inflammatory Phenotype of Regulatory Macrophages by Downregulating the Production of Interleukin (IL)-23 and IL-22. Front Immunol, 8:771.
[10]
Rogerio AP, Haworth O, Croze R, Oh SF, Uddin M, Carlo T, et al. (2012). Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses. J Immunol, 189:1983-1991.
[11]
Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD (2008) Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat Immunol, 9: 873-879.
[12]
Spite M, Norling LV, Summers L, Yang R, Cooper D, Petasis NA, et al. (2009). Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature, 461:1287-1291.
[13]
Yang FY, Chen R, Zhang X, Huang B, Tsang LL, Li X, Jiang X (2018). Preconditioning enhances the therapeutic effects of mesenchymal stem cells on colitis through PGE2-mediated T-cell modulation. Cell Transplant, 27(9): 1352-1367.
[14]
Yang HM, Song WJ, Li Q, et al. (2018). Canine mesenchymal stem cells treated with TNF-α and IFN-γ enhance anti-inflammatory effects through the COX-2/PGE2 pathway. Res Vet Sci, 119: 19-26.
[15]
Wang B, Lin Y, Hu Y, Shan W, et al. (2017). mTOR inhibition improves the immunomodulatory properties of human bone marrow mesenchymal stem cells by inducing COX-2 and PGE2. Stem Cell Res Ther, 8: 292.
[16]
Kim DS, Lee WH, Lee MW, et al. (2018). Involvement of TLR3-Dependent PGES Expression in Immunosuppression by Human Bone Marrow Mesenchymal Stem Cells. Stem Cell Rev Rep, 14: 286-293.
[17]
Vasandan AB, Jahnavi S, Shashank C, Prasad P, Kumar A, Prasanna SJ (2016) Human Mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep, 6: 38308.
[18]
Park HJ, Kim J, Saima FT, Rhee KJ, Hwang S, Kim MY, Baik SK, Eom YW, Kim HS (2018). Adipose-derived stem cells ameliorate colitis by suppression of inflammasome formation and regulation of M1-macrophage population through prostaglandin E2. Biochem Biophys Res Commun, 498: 988-995.
[19]
An JH, Song WJ, Li Q, Kim SM, Yang JI, Ryu MO, Nam AR, Bhang DH, Jung YC, Youn HY (2018). Prostaglandin E2 secreted from feline adipose tissue-derived mesenchymal stem cells alleviate DSS-induced colitis by increasing regulatory T cells in mice. BMC Vet Res, 14: 354.
[20]
Rozenberg A, Rezk A, Boivin MN, et al. (2016). Human mesenchymal stem cells impact Th17 and Th1 responses through a prostaglandin E2 and myeloid-dependent mechanism. Stem Cells Transl Med, 5: 1506-1514.
[21]
Wang L, Zhao Y, Shi S (2012). Interplay between mesenchymal stem cells and lymphocytes: implications for immunotherapy and tissue regeneration. J Dent Res, 91: 1003-1010.
[22]
Duffy MM, Ritter T, Ceredig R, Griffin MD (2011). Mesenchymal stem cell effects on T-cell effector pathways. Stem Cell Res Ther, 2(4): 34.
[23]
Engela AU, Baan CC, Litjens NH, Franquesa M, Betjes MG, Weimar W, Hoogduijn MJ (2013). Mesenchymal stem cells control alloreactive CD8(+) CD28(-) T cells. Clin Exp Immunol, 174: 449-458.
[24]
Li M, Sun X, Kuang X, Liao Y, Li H, Luo D (2014). Mesenchymal stem cells suppress CD8+ T cell-mediated activation by suppressing natural killer group 2, member D protein receptor expression and secretion of prostaglandin E2, indoleamine 2, 3-dioxygenase and transforming growth factor-beta. Clin Exp Immunol, 178: 516-524.
[25]
Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL (2011). Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci, 18: 49.
[26]
Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, Pennesi G (2005). Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol, 35(5):1482-1490.
[27]
Corcione A, Benvenuto F, Ferretti E, et al. (2006). Human mesenchymal stem cells modulate B-cell functions. Blood, 107(1): 367-372.
[28]
Wang LT, Ting CH, Yen ML, Liu KJ, Sytwu HK, Wu KK, Yen BL (2016). Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci, 23: 76.
[29]
Wang M, Honn KV, Nie D (2007). Cyclooxygenases, prostanoids, and tumor progression. Cancer Metastasis Rev, 26: 525.
[30]
Phipps RP, Stein SH, Roper RL (1991). A new view of prostaglandin E regulation of the immune response. Immunol Today, 12: 349-352.
[31]
Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, et al. (2009). Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 15: 42-49.
[32]
Ylöstalo JH, Bartosh TJ, Coble K, Prockop DJ (2012). Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an antiinflammatory phenotype. Stem Cells, 30: 2283-2296.
[33]
Chiossone L, Conte R, Spaggiari GM, Serra M, Romei C, Bellora F, et al (2016). Mesenchymal stromal cells induce peculiar alternatively activated macrophages capable of dampening both innate and adaptive immune responses. Stem Cells, 34: 1909-1921.
[34]
Poloso NJ, Urquhart P, Nicolaou A, Wang J, Woodward DF (2013). PGE2 differentially regulates monocyte-derived dendritic cell cytokine responses depending on receptor usage (EP2/EP4). Mol Immunol, 54: 284-295.
[35]
Kalim KW, Groettrup M (2013). Prostaglandin E2 inhibits IL-23 and IL-12 production by human monocytes through down-regulation of their common p40 subunit. Mol Immunol, 53: 274-282.
[36]
Liu X, Qu X, Chen Y, Liao L, Cheng K, Shao C, et al (2012). Mesenchymal stem/ stromal cells induce the generation of novel IL-10-dependent regulatory dendritic cells by SOCS3 activation. J Immunol, 189: 1182-1192.
[37]
Loynes CA, Lee JA, Robertson AL, Steel MJ, et al. (2018). PGE2 production at sites of tissue injury promotes an anti-inflammatory neutrophil phenotype and determines the outcome of inflammation resolution in vivo. Sci Adv, 4(9):eaar8320.
[38]
Chan MM-Y, Moore AR (2010). Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J Immunol, 184: 6418-6426.
[39]
Das UN (2010). Current and emerging strategies for the treatment and management of systemic lupus erythematosus based on molecular signatures of acute and chronic inflammation. J Inflammation Res, 3: 143-170.
[40]
Das UN (2011). Molecular Basis of Health and Disease. Springer, New York, 2011.
[41]
Zhang Y, Desai A, Yang SY, et al (2015). Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science, 348: 1223.
[42]
North TE, Goessling W, Walkley CR, et al. (2007). Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature, 447: 1007-1011.
[43]
Li F, Huang Q, Chen J, et al. (2010). Apoptotic cells activate the “Phoenix Rising” pathway to promote wound healing and tissue regeneration. Sci Signal, 3(110): ra13.
[44]
Hoggatt J, Mohammad KS, Singh P, et al. (2013). Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature, 495:365-369
[45]
Diaz MF, Li N, Lee HJ, et al. (2015). Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J Exp Med, 212: 665-680.
[46]
Das UN (2018). Arachidonic acid and other unsaturated fatty acids and some of their metabolites function as endogenous antimicrobial molecules: A review. J Adv Res, 11: 57-66.
[47]
Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD, Matthay MA (2015) Human Mesenchymal Stem (Stromal) Cells Promote the Resolution of Acute Lung Injury in Part through Lipoxin A4. J Immunol, 195: 875-881.
[48]
Cheng X, He S, Yuan J, Miao S, Gao H, Zhang J, Li Y, Peng W, Wu P (2016). Lipoxin A4 attenuates LPS-induced mouse acute lung injury via Nrf2-mediated E-cadherin expression in airway epithelial cells. Free Radic Biol Med, 93: 52-66.
[49]
Bai Y, Wang J, He Z, Yang M, Li L, Jiang H (2019). Mesenchymal stem cells reverse diabetic nephropathy disease via lipoxin A4 by targeting transforming growth factor β (TGF-β)/smad pathway and pro-Inflammatory cytokines. Med Sci Monit, 25: 3069-3076.
[50]
Suresh Y, Das UN (2001). Protective action of arachidonic acid against alloxan-induced cytotoxicity and diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids, 64: 37-52.
[51]
Suresh Y, Das UN (2003). Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: Effect of ω-6 fatty acids. Nutrition, 19: 93-114.
[52]
Suresh Y, Das UN (2003). Long-chain polyunsaturated fatty acids and chemically-induced diabetes mellitus: Effect of ω-3 fatty acids. Nutrition, 19: 213-228.
[53]
Naveen KVG, Naidu VGM, Das UN (2017). Arachidonic acid and lipoxin A4 attenuate alloxan-induced cytotoxicity to RIN5F cells in vitro and type 1 diabetes mellitus in vivo. BioFactors, 43: 251-271.
[54]
Naveen KVG, Naidu VGM, Das UN (2017). Arachidonic acid and lipoxin A4 attenuate streptozotocin-induced cytotoxicity to RIN5F cells in vitro and type 1 and type 2 diabetes mellitus in vivo. Nutrition. 2017; 35: 61-80.
[55]
Naveen KVG, Naidu GVM, Das UN (2018). Amelioration of streptozotocin-induced type 2 diabetes mellitus in Wistar rats by arachidonic acid. Biochem Biophys Res Commun, 496: 105-113.
[56]
Siresha B, Das UN (2019). PUFAs, BDNF and lipoxin A4 inhibit chemical-induced cytotoxicity of RIN5F cells in vitro and streptozotocin-induced type 2 diabetes mellitus in vivo. Lipids Health Dis, 18: 214.
[57]
Vane JR, Botting RM (2003). The mechanism of action of aspirin. Thromb Res, 110: 255-258.
[58]
Coulombe F, Jaworska J, Verway M, et al. (2014). Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages. Immunity, 40: 554-568.
[59]
Spaggiari GM, Capobianco A, Abdelrazik H, et al. (2008). Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood, 111: 1327-1333.
Barzilai Nir,Appleby James C,Austad Steven N,Cuervo Ana Maria,Kaeberlein Matt,Gonzalez-Billault Christian,Lederman Stephanie,Stambler Ilia,Sierra Felipe. Geroscience in the Age of COVID-19[J]. Aging and disease, 2020, 11(4): 725-729.