Advertisement
FULL-LENGTH ARTICLE | Basic Research| Volume 24, ISSUE 6, P608-618, June 2022

Download started.

Ok

Characterizing human mesenchymal stromal cells’ immune-modulatory potency using targeted lipidomic profiling of sphingolipids

  • Author Footnotes
    † Co-first authors.
    S'Dravious A. DeVeaux
    Footnotes
    † Co-first authors.
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Author Footnotes
    † Co-first authors.
    Molly E. Ogle
    Footnotes
    † Co-first authors.
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Sofiya Vyshnya
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Nathan F. Chiappa
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Bobby Leitmann
    Affiliations
    Regenerative Bioscience Center, Rhodes Center for ADS, University of Georgia, Athens, GA

    School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA
    Search for articles by this author
  • Ryan Rudy
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Abigail Day
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Luke J. Mortensen
    Affiliations
    Regenerative Bioscience Center, Rhodes Center for ADS, University of Georgia, Athens, GA

    School of Chemical, Materials and Biomedical Engineering, University of Georgia, Athens, GA
    Search for articles by this author
  • Joanne Kurtzberg
    Affiliations
    Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, NC
    Search for articles by this author
  • Krishnendu Roy
    Correspondence
    Corresponding authors: Krishnendu Roy: Krone Engineered Biosystems Building, 950 Atlantic Drive, Atlanta, GA 30332, Edward Botchwey: Parker H. Petit Institute for Bioengineering & Bioscience, 315 Ferst Drive, Atlanta, GA, 30332.
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology, Atlanta, GA

    NSF Engineering Research Center (ERC) for Cell Manufacturing Technologies (CMaT), Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Edward A. Botchwey
    Correspondence
    Corresponding authors: Krishnendu Roy: Krone Engineered Biosystems Building, 950 Atlantic Drive, Atlanta, GA 30332, Edward Botchwey: Parker H. Petit Institute for Bioengineering & Bioscience, 315 Ferst Drive, Atlanta, GA, 30332.
    Affiliations
    The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory, Atlanta, GA

    Petit Institute of Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, GA
    Search for articles by this author
  • Author Footnotes
    † Co-first authors.
Published:February 19, 2022DOI:https://doi.org/10.1016/j.jcyt.2021.12.009

      Abstract

      Cell therapies are expected to increase over the next decade owing to increasing demand for clinical applications. Mesenchymal stromal cells (MSCs) have been explored to treat a number of diseases, with some successes in early clinical trials. Despite early successes, poor MSC characterization results in lessened therapeutic capacity once in vivo. Here, we characterized MSCs derived from bone marrow (BM), adipose tissue and umbilical cord tissue for sphingolipids (SLs), a class of bioactive lipids, using liquid chromatography/tandem mass spectrometry. We found that ceramide levels differed based on the donor's sex in BM-MSCs. We detected fatty acyl chain variants in MSCs from all three sources. Linear discriminant analysis revealed that MSCs separated based on tissue source. Principal component analysis showed that interferon-γ–primed and unstimulated MSCs separated according to their SL signature. Lastly, we detected higher ceramide levels in low indoleamine 2,3-dioxygenase MSCs, indicating that sphingomyelinase or ceramidase enzymatic activity may be involved in their immune potency.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pereira Chilima T.D.
        • Moncaubeig F.
        • Farid S.S.
        Impact of allogeneic stem cell manufacturing decisions on cost of goods, process robustness and reimbursement.
        Biochemical Engineering Journal. 2018; 137: 132-151
        • Mason C.
        • Brindley D.A.
        • Culme-Seymour E.J.
        • Davie N.L.
        Cell therapy industry: billion dollar global business with unlimited potential.
        Regen Med. 2011; 6: 265-272
        • Fischbach M.A.
        • Bluestone J.A.
        • Lim W.A.
        Cell-based therapeutics: the next pillar of medicine.
        Sci Transl Med. 2013; 5: 179ps7
        • Rao M.
        • Mason C.
        • Solomon S.
        Cell therapy worldwide: an incipient revolution.
        Regen Med. 2015; 10: 181-191
        • Wang M.
        • Yuan Q.
        • Xie L.
        Mesenchymal Stem Cell-Based Immunomodulation: Properties and Clinical Application.
        Stem Cells International. 2018; 20183057624
        • Cosenza S.
        • Toupet K.
        • Maumus M.
        • Luz-Crawford P.
        • Blanc-Brude O.
        • Jorgensen C.
        • Noël D.
        Mesenchymal stem cells-derived exosomes are more immunosuppressive than microparticles in inflammatory arthritis.
        Theranostics. 2018; 8: 1399-1410
        • Blaess M.
        • Deigner H.P.
        Derailed Ceramide Metabolism in Atopic Dermatitis (AD): A Causal Starting Point for a Personalized (Basic) Therapy.
        Int J Mol Sci. 2019; 16
        • Ahn E.H.
        • Lee M.B.
        • Seo D.J.
        • Lee J.
        • Kim Y.
        • Gupta K.
        Sphingosine Induces Apoptosis and Down-regulation of MYCN in PAX3-FOXO1-positive Alveolar Rhabdomyosarcoma Cells Irrespective of TP53 Mutation.
        Anticancer Res. 2018; 38: 71-76
        • Galipeau J.
        Mesenchymal Stromal Cells for Graft-versus-Host Disease: A Trilogy.
        Biology of Blood and Marrow Transplantation. 2020; 26: e89-e91
        • Sanjucta A.
        • Sayani M.
        • Dwaipayan S.
        Mesenchymal Stem Cell as a Potential Therapeutic for Inflammatory Bowel Disease- Myth or Reality?.
        Current Stem Cell Research & Therapy. 2017; 12: 644-657
        • Bagno L.
        • Hatzistergos K.E.
        • Balkan W.
        • Hare J.M.
        Mesenchymal Stem Cell-Based Therapy for Cardiovascular Disease: Progress and Challenges.
        Mol Ther. 2018; 26: 1610-1623
        • Sisakhtnezhad S.
        • Alimoradi E.
        • Akrami H.
        External factors influencing mesenchymal stem cell fate in vitro.
        Eur J Cell Biol. 2017; 96: 13-33
        • Phinney D.G.
        • Galipeau J.
        Manufacturing mesenchymal stromal cells for clinical applications: A survey of Good Manufacturing Practices at US academic centers.
        Cytotherapy. 2019; 21: 782-792
        • Mendicino M.
        • Bailey Alexander M.
        • Wonnacott K.
        • Puri Raj K.
        • Bauer Steven R.
        MSC-Based Product Characterization for Clinical Trials: An FDA Perspective.
        Cell Stem Cell. 2014; 14: 141-145
        • Dominici M.
        • Le Blanc K.
        • Mueller I.
        • Slaper-Cortenbach I.
        • Marini F.
        • Krause D.
        • Deans R.
        • Keating A.
        • Prockop D.
        • Horwitz E.
        Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
        Cytotherapy. 2006; 8: 315-317
        • Viswanathan S.
        • Shi Y.
        • Galipeau J.
        • Krampera M.
        • Leblanc K.
        • Martin I.
        • Nolta J.
        • Phinney D.G.
        • Sensebe L.
        Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT®) Mesenchymal Stromal Cell committee position statement on nomenclature.
        Cytotherapy. 2019; 21: 1019-1024
        • McCartney A.
        • Vignoli A.
        • Biganzoli L.
        • Love R.
        • Tenori L.
        • Luchinat C.
        • Di Leo A.
        Metabolomics in breast cancer: A decade in review.
        Cancer Treatment Reviews. 2018; 67: 88-96
        • Gowda G.A.N.
        • Djukovic D.
        Overview of mass spectrometry-based metabolomics: opportunities and challenges.
        Methods Mol Biol. 2014; 1198: 3-12
        • Ren J.-L.
        • Zhang A.-H.
        • Kong L.
        • Wang X.-J.
        Advances in mass spectrometry-based metabolomics for investigation of metabolites.
        RSC Advances. 2018; 8: 22335-22350
        • Emwas A.-H.
        • Roy R.
        • McKay R.T.
        • Tenori L.
        • Saccenti E.
        • Gowda G.A.N.
        • Raftery D.
        • Alahmari F.
        • Jaremko L.
        • Jaremko M.
        • Wishart D.S.
        NMR Spectroscopy for Metabolomics Research.
        Metabolites. 2019; 9: 123
        • León Z.
        • García-Cañaveras J.C.
        • Donato M.T.
        • Lahoz A.
        Mammalian cell metabolomics: experimental design and sample preparation.
        Electrophoresis. 2013; 34: 2762-2775
        • Kalluri U.
        • Naiker M.
        • Myers M.A.
        Cell culture metabolomics in the diagnosis of lung cancer-the influence of cell culture conditions.
        J Breath Res. 2014; 8027109
        • Muschet C.
        • Möller G.
        • Prehn C.
        • de Angelis M.H.
        • Adamski J.
        • Tokarz J.
        Removing the bottlenecks of cell culture metabolomics: fast normalization procedure, correlation of metabolites to cell number, and impact of the cell harvesting method.
        Metabolomics. 2016; 12 (151-151)
        • O'Donnell V.B.
        • Ekroos K.
        • Liebisch G.
        • Wakelam M.
        Lipidomics: Current state of the art in a fast moving field.
        Wiley Interdiscip Rev Syst Biol Med. 2020; 12: e1466
        • Leuti A.
        • Fazio D.
        • Fava M.
        • Piccoli A.
        • Oddi S.
        • Maccarrone M.
        Bioactive lipids, inflammation and chronic diseases.
        Advanced Drug Delivery Reviews. 2020;
        • Musso G.
        • Cassader M.
        • Paschetta E.
        • Gambino R.
        Bioactive lipid species and metabolic pathways in progression and resolution of nonalcoholic steatohepatitis.
        Gastroenterology. 2018; 155 (e8): 282-302
        • Hannun Y.A.
        • Obeid L.M.
        Sphingolipids and their metabolism in physiology and disease.
        Nature reviews Molecular cell biology. 2018; 19: 175
        • Verderio C.
        • Gabrielli M.
        • Giussani P.
        Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles.
        J Lipid Res. 2018; 59: 1325-1340
        • Marycz K.
        • Śmieszek A.
        • Jeleń M.
        • Chrząstek K.
        • Grzesiak J.
        • Meissner J.
        The effect of the bioactive sphingolipids S1P and C1P on multipotent stromal cells–new opportunities in regenerative medicine.
        Cellular and Molecular Biology Letters. 2015; 20: 510-533
        • Marycz K.
        • Krzak J.
        • Maredziak M.
        • Tomaszewski K.A.
        • Szczurek A.
        • Moszak K.
        The influence of metal-based biomaterials functionalized with sphingosine-1-phosphate on the cellular response and osteogenic differentaion potenial of human adipose derived mesenchymal stem cells in vitro.
        J Biomater Appl. 2016; 30: 1517-1533
        • Campos A.M.
        • Maciel E.
        • Moreira A.S.P.
        • Sousa B.
        • Melo T.
        • Domingues P.
        • Curado L.
        • Antunes B.
        • Domingues M.R.M.
        • Santos F.
        Lipidomics of Mesenchymal Stromal Cells: Understanding the Adaptation of Phospholipid Profile in Response to Pro-Inflammatory Cytokines.
        Journal of Cellular Physiology. 2016; 231: 1024-1032
        • Ogle M.E.
        • Sefcik L.S.
        • Awojoodu A.O.
        • Chiappa N.F.
        • Lynch K.
        • Peirce-Cottler S.
        • Botchwey E.A.
        Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning.
        Acta Biomaterialia. 2014; 10: 4704-4714
        • Hannun Y.A.
        • Obeid L.M.
        Principles of bioactive lipid signalling: lessons from sphingolipids.
        Nat Rev Mol Cell Biol. 2008; 9: 139-150
        • Gupta S.
        • Maurya M.R.
        • Merrill Jr., A.H.
        • Glass C.K.
        • Subramaniam S.
        Integration of lipidomics and transcriptomics data towards a systems biology model of sphingolipid metabolism.
        BMC Syst Biol. 2011; 5: 26
        • Hernandez-Corbacho M.J.
        • Salama M.F.
        • Canals D.
        • Senkal C.E.
        • Obeid L.M.
        Sphingolipids in mitochondria.
        Biochim Biophys Acta. 2017; 1862: 56-68
        • Montgomery M.K.
        • Brown S.H.
        • Lim X.Y.
        • Fiveash C.E.
        • Osborne B.
        • Bentley N.L.
        • Braude J.P.
        • Mitchell T.W.
        • Coster A.C.
        • Don A.S.
        Regulation of glucose homeostasis and insulin action by ceramide acyl-chain length: A beneficial role for very long-chain sphingolipid species.
        Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2016; 1861: 1828-1839
        • Wattenberg B.W.
        The long and the short of ceramides.
        Journal of Biological Chemistry. 2018; 293: 9922-9923
        • Mándi Y.
        • Vécsei L.
        The kynurenine system and immunoregulation.
        Journal of neural transmission. 2012; 119: 197-209
        • Jürgens B.
        • Hainz U.
        • Fuchs D.
        • Felzmann T.
        • Heitger A.
        Interferon-gamma-triggered indoleamine 2,3-dioxygenase competence in human monocyte-derived dendritic cells induces regulatory activity in allogeneic T cells.
        Blood. 2009; 114: 3235-3243
        • Kim S.-J.
        • Magnani A.
        • Boyd S.
        Robust fisher discriminant analysis.
        Advances in neural information processing systems. 2006; : 659-666
        • Marchevsky A.M.
        • Tsou J.A.
        • Laird-Offringa I.A.
        Classification of individual lung cancer cell lines based on DNA methylation markers: use of linear discriminant analysis and artificial neural networks.
        The Journal of Molecular Diagnostics. 2004; 6: 28-36
        • Al-Dulaimi K.
        • Chandran V.
        • Nguyen K.
        • Banks J.
        • Tomeo-Reyes I.
        Benchmarking HEp-2 specimen cells classification using linear discriminant analysis on higher order spectra features of cell shape.
        Pattern Recognition Letters. 2019; 125: 534-541
        • Tang M.
        • Xia L.
        • Wei D.
        • Yan S.
        • Du C.
        • Cui H.-L.
        Distinguishing different cancerous human cells by raman spectroscopy based on discriminant analysis methods.
        Applied Sciences. 2017; 7: 900
        • Spincemaille P.
        • Cammue B.P.
        • Thevissen K.
        Sphingolipids and mitochondrial function, lessons learned from yeast.
        Microbial Cell. 2014; 1: 210-224
        • Patwardhan G.A.
        • Beverly L.J.
        • Siskind L.J.
        Sphingolipids and mitochondrial apoptosis.
        J Bioenerg Biomembr. 2016; 48: 153-168
        • Selma J.M.
        • Das A.
        • Awojoodu A.O.
        • Wang T.
        • Kaushik A.P.
        • Cui Q.
        • Song H.
        • Ogle M.E.
        • Olingy C.E.
        • Pendleton E.G.
        • Tehrani K.F.
        • Mortensen L.J.
        • Botchwey E.A.
        Novel Lipid Signaling Mediators for Mesenchymal Stem Cell Mobilization during Bone Repair.
        Cell Mol Bioeng. 2018; 11: 241-253
        • Ogle M.E.
        • Olingy C.E.
        • Awojoodu A.O.
        • Das A.
        • Ortiz R.A.
        • Cheung H.Y.
        • Botchwey E.A.
        Sphingosine-1-Phosphate Receptor-3 Supports Hematopoietic Stem and Progenitor Cell Residence Within the Bone Marrow Niche.
        Stem Cells. 2017; 35: 1040-1052
        • Dadsena S.
        • Bockelmann S.
        • Mina J.G.M.
        • Hassan D.G.
        • Korneev S.
        • Razzera G.
        • Jahn H.
        • Niekamp P.
        • Müller D.
        • Schneider M.
        • Tafesse F.G.
        • Marrink S.J.
        • Melo M.N.
        • Holthuis J.C.M.
        Ceramides bind VDAC2 to trigger mitochondrial apoptosis.
        Nature Communications. 2019; 10: 1832
        • Mielke M.M.
        • Bandaru V.V.R.
        • Han D.
        • An Y.
        • Resnick S.M.
        • Ferrucci L.
        • Haughey N.J.
        Demographic and clinical variables affecting mid-to late-life trajectories of plasma ceramide and dihydroceramide species.
        Aging cell. 2015; 14: 1014-1023
        • Norheim F.
        • Bjellaas T.
        • Hui S.T.
        • Krishnan K.C.
        • Lee J.
        • Gupta S.
        • Pan C.
        • Hasin-Brumshtein Y.
        • Parks B.W.
        • Li D.Y.
        Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR.
        J Lipid Res. 2018; 59: 1164-1174
        • Krishnan K.C.
        • Mehrabian M.
        • Lusis A.J.
        Sex differences in metabolism and cardiometabolic disorders.
        Current opinion in lipidology. 2018; 29: 404
        • Li Y.
        • Zhang W.
        • Li J.
        • Sun Y.
        • Yang Q.
        • Wang S.
        • Luo X.
        • Wang W.
        • Wang K.
        • Bai W.
        • Zhang H.
        • Qin L.
        The imbalance in the aortic ceramide/sphingosine-1-phosphate rheostat in ovariectomized rats and the preventive effect of estrogen.
        Lipids in Health and Disease. 2020; 19: 95
        • Polchert D.
        • Sobinsky J.
        • Douglas G.
        • Kidd M.
        • Moadsiri A.
        • Reina E.
        • Genrich K.
        • Mehrotra S.
        • Setty S.
        • Smith B.
        • Bartholomew A.
        IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease.
        Eur J Immunol. 2008; 38: 1745-1755
        • Zhai L.
        • Bell A.
        • Ladomersky E.
        • Lauing K.L.
        • Bollu L.
        • Sosman J.A.
        • Zhang B.
        • Wu J.D.
        • Miller S.D.
        • Meeks J.J.
        • Lukas R.V.
        • Wyatt E.
        • Doglio L.
        • Schiltz G.E.
        • McCusker R.H.
        • Wainwright D.A.
        Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies.
        Frontiers in Immunology. 2020; 11: 1185
        • Mbongue J.C.
        • Nicholas D.A.
        • Torrez T.W.
        • Kim N.-S.
        • Firek A.F.
        • Langridge W.H.R.
        The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity.
        Vaccines (Basel). 2015; 3: 703-729
        • Gray A.
        • Schloss R.S.
        • Yarmush M.
        Donor variability among anti-inflammatory pre-activated mesenchymal stromal cells.
        Technology (Singap World Sci). 2016; 4: 201-215
        • Ballou L.R.
        • Laulederkind S.J.
        • Rosloniec E.F.
        • Raghow R.
        Ceramide signalling and the immune response.
        Biochimica et Biophysica Acta (BBA)-Lipids and Lipid Metabolism. 1996; 1301: 273-287
        • Jrad-Lamine A.
        • Henry-Berger J.
        • Damon-Soubeyrand C.
        • Saez F.
        • Kocer A.
        • Janny L.
        • Pons-Rejraji H.
        • Munn D.H.
        • Mellor A.L.
        • Gharbi N.
        • Cadet R.
        • Guiton R.
        • Aitken R.J.
        • Drevet J.R.
        Indoleamine 2,3-dioxygenase 1 (ido1) is involved in the control of mouse caput epididymis immune environment.
        PLoS One. 2013; 8 (e66494-e66494)
        • Zanoni P.
        • Khetarpal S.A.
        • Larach D.B.
        • Hancock-Cerutti W.F.
        • Millar J.S.
        • Cuchel M.
        • DerOhannessian S.
        • Kontush A.
        • Surendran P.
        • Saleheen D.
        • Trompet S.
        • Jukema J.W.
        • De Craen A.
        • Deloukas P.
        • Sattar N.
        • Ford I.
        • Packard C.
        • Majumder A.a.S.
        • Alam D.S.
        • Di Angelantonio E.
        • Abecasis G.
        • Chowdhury R.
        • Erdmann J.
        • Nordestgaard B.G.
        • Nielsen S.F.
        • Tybjærg-Hansen A.
        • Schmidt R.F.
        • Kuulasmaa K.
        • Liu D.J.
        • Perola M.
        • Blankenberg S.
        • Salomaa V.
        • Männistö S.
        • Amouyel P.
        • Arveiler D.
        • Ferrieres J.
        • Müller-Nurasyid M.
        • Ferrario M.
        • Kee F.
        • Willer C.J.
        • Samani N.
        • Schunkert H.
        • Butterworth A.S.
        • Howson J.M.M.
        • Peloso G.M.
        • Stitziel N.O.
        • Danesh J.
        • Kathiresan S.
        • Rader D.J.
        Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease.
        Science. 2016; 351: 1166
        • Toth P.P.
        • Granowitz C.
        • Hull M.
        • Liassou D.
        • Anderson A.
        • Philip S.
        High triglycerides are associated with increased cardiovascular events, medical costs, and resource use: a real-world administrative claims analysis of statin-treated patients with high residual cardiovascular risk.
        Journal of the American Heart Association. 2018; 7e008740
        • Kraft M.L.
        Sphingolipid Organization in the Plasma Membrane and the Mechanisms That Influence It.
        Front Cell Dev Biol. 2016; 4: 154
        • Zeidan Y.H.
        • Jenkins R.W.
        • Hannun Y.A.
        Remodeling of cellular cytoskeleton by the acid sphingomyelinase/ceramide pathway.
        J Cell Biol. 2008; 181: 335-350
        • Slotte J.
        Molecular properties of various structurally defined sphingomyelins – Correlation of structure with function.
        Progress in Lipid Research. 2013; 52: 206-219
        • Slotte J.P.
        Biological functions of sphingomyelins.
        Progress in Lipid Research. 2013; 52: 424-437
        • Alexaki A.
        • Clarke B.A.
        • Gavrilova O.
        • Ma Y.
        • Zhu H.
        • Ma X.
        • Xu L.
        • Tuymetova G.
        • Larman B.C.
        • Allende M.L.
        De novo sphingolipid biosynthesis is required for adipocyte survival and metabolic homeostasis.
        Journal of Biological Chemistry. 2017; 292: 3929-3939
        • Pradas I.
        • Huynh K.
        • Cabre R.
        • Ayala V.
        • Meikle P.J.
        • Jove M.
        • Pamplona R.
        Lipidomics Reveals a Tissue-Specific Fingerprint.
        Front Physiol. 2018; 9: 1165
        • Jennemann R.
        • Kaden S.
        • Sandhoff R.
        • Nordström V.
        • Wang S.
        • Volz M.
        • Robine S.
        • Amen N.
        • Rothermel U.
        • Wiegandt H.
        Glycosphingolipids are essential for intestinal endocytic function.
        Journal of Biological Chemistry. 2012; 287: 32598-32616
        • Popovic Z.V.
        • Rabionet M.
        • Jennemann R.
        • Krunic D.
        • Sandhoff R.
        • Gröne H.-J.
        • Porubsky S.
        Glucosylceramide synthase is involved in development of invariant natural killer T cells.
        Frontiers in immunology. 2017; 8: 848
        • Jennemann R.
        • Sandhoff R.
        • Wang S.
        • Kiss E.
        • Gretz N.
        • Zuliani C.
        • Martin-Villalba A.
        • Jäger R.
        • Schorle H.
        • Kenzelmann M.
        Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth.
        Proceedings of the National Academy of Sciences. 2005; 102: 12459-12464
        • Zhao Z.
        • Chen Z.
        • Zhao X.
        • Pan F.
        • Cai M.
        • Wang T.
        • Zhang H.
        • Lu J.R.
        • Lei M.
        Sphingosine-1-phosphate promotes the differentiation of human umbilical cord mesenchymal stem cells into cardiomyocytes under the designated culturing conditions.
        Journal of Biomedical Science. 2011; 18: 37
        • Laviad E.L.
        • Albee L.
        • Pankova-Kholmyansky I.
        • Epstein S.
        • Park H.
        • Merrill Jr., A.H.
        • Futerman A.H.
        Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate.
        J Biol Chem. 2008; 283: 5677-5684
        • Gault C.R.
        • Obeid L.M.
        • Hannun Y.A.
        An overview of sphingolipid metabolism: from synthesis to breakdown.
        Adv Exp Med Biol. 2010; 688: 1-23
        • Riebeling C.
        • Allegood J.C.
        • Wang E.
        • Merrill Jr., A.H.
        • Futerman A.H.
        Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors.
        J Biol Chem. 2003; 278: 43452-43459
        • Mizutani Y.
        • Kihara A.
        • Igarashi Y.
        Mammalian Lass6 and its related family members regulate synthesis of specific ceramides.
        Biochem J. 2005; 390: 263-271
        • Soupene E.
        • Serikov V.
        • Kuypers F.A.
        Characterization of an acyl-coenzyme A binding protein predominantly expressed in human primitive progenitor cells.
        J Lipid Res. 2008; 49: 1103-1112
        • Cartier A.
        • Hla T.
        Sphingosine 1-phosphate: Lipid signaling in pathology and therapy.
        Science. 2019; 366: 6463
        • Merrill Jr., A.H.
        • Wang E.
        • Mullins R.E.
        • Jamison W.C.
        • Nimkar S.
        • Liotta D.C.
        Quantitation of free sphingosine in liver by high-performance liquid chromatography.
        Anal Biochem. 1988; 171: 373-381
        • Zheng W.
        • Kollmeyer J.
        • Symolon H.
        • Momin A.
        • Munter E.
        • Wang E.
        • Kelly S.
        • Allegood J.C.
        • Liu Y.
        • Peng Q.
        • Ramaraju H.
        • Sullards M.C.
        • Cabot M.
        • Merrill Jr., A.H.
        Ceramides and other bioactive sphingolipid backbones in health and disease: lipidomic analysis, metabolism and roles in membrane structure, dynamics, signaling and autophagy.
        Biochim Biophys Acta. 2006; 1758: 1864-1884
        • Merrill Jr., A.H.
        • Sullards M.C.
        Opinion article on lipidomics: Inherent challenges of lipidomic analysis of sphingolipids.
        Biochim Biophys Acta. 2017;
        • Hait N.C.
        • Maiti A.
        The role of sphingosine-1-phosphate and ceramide-1-phosphate in inflammation and cancer.
        Mediators of inflammation. 2017; 2017
        • Gomez-Munoz A.
        • Presa N.
        • Gomez-Larrauri A.
        • Rivera I.-G.
        • Trueba M.
        • Ordonez M.
        Control of inflammatory responses by ceramide, sphingosine 1-phosphate and ceramide 1-phosphate.
        Progress in lipid research. 2016; 61: 51-62
        • Yuan X.
        • Logan T.M.
        • Ma T.
        Metabolism in Human Mesenchymal Stromal Cells: A Missing Link Between hMSC Biomanufacturing and Therapy?.
        Frontiers in immunology. 2019; : 10
        • Pandey S.
        • Banks K.M.
        • Kumar R.
        • Kuo A.
        • Wen D.
        • Hla T.
        • Evans T.
        Sphingosine Kinases Protect Murine ESCs from Sphingosine-induced Cell Cycle Arrest.
        STEM CELLS. 2020;
        • Puig N.
        • Estruch M.
        • Jin L.
        • Sanchez-Quesada J.L.
        • Benitez S.
        The Role of Distinctive Sphingolipids in the Inflammatory and Apoptotic Effects of Electronegative LDL on Monocytes.
        Biomolecules. 2019; 9: 300
        • Luheshi N.M.
        • Giles J.A.
        • Lopez-Castejon G.
        • Brough D.
        Sphingosine regulates the NLRP3-inflammasome and IL-1β release from macrophages.
        Eur J Immunol. 2012; 42: 716-725
        • Aoki M.
        • Aoki H.
        • Ramanathan R.
        • Hait N.C.
        • Takabe K.
        Sphingosine-1-phosphate signaling in immune cells and inflammation: roles and therapeutic potential.
        Mediators of inflammation. 2016; 2016
        • Obinata H.
        • Hla T.
        Sphingosine 1-phosphate and inflammation.
        International immunology. 2019; 31: 617-625
        • Lidgerwood G.E.
        • Pitson S.M.
        • Bonder C.
        • Pebay A.
        Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology.
        Progress in lipid research. 2018; 72: 42-54
        • Chen R.
        • Cai X.
        • Liu J.
        • Bai B.
        • Li X.
        Sphingosine 1-phosphate promotes mesenchymal stem cell-mediated cardioprotection against myocardial infarction via ERK1/2-MMP-9 and Akt signaling axis.
        Life sciences. 2018; 215: 31-42
        • Yuan X.
        • Li D.
        • Chen X.
        • Han C.
        • Xu L.
        • Huang T.
        • Dong Z.
        • Zhang M.
        Extracellular vesicles from human-induced pluripotent stem cell-derived mesenchymal stromal cells (hiPSC-MSCs) protect against renal ischemia/reperfusion injury via delivering specificity protein (SP1) and transcriptional activating of sphingosine kinase 1 and inhibiting necroptosis.
        Cell Death & Disease. 2017; 8: 3200
        • Prymas K.
        • Świątkowska A.
        • Traczyk G.
        • Ziemlińska E.
        • Dziewulska A.
        • Ciesielska A.
        • Kwiatkowska K.
        Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide.
        Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids. 2020; 1865158549
        • Sakamoto H.
        • Yoshida T.
        • Sanaki T.
        • Shigaki S.
        • Morita H.
        • Oyama M.
        • Mitsui M.
        • Tanaka Y.
        • Nakano T.
        • Mitsutake S.
        Possible roles of long-chain sphingomyelines and sphingomyelin synthase 2 in mouse macrophage inflammatory response.
        Biochemical and biophysical research communications. 2017; 482: 202-207
        • Norris G.H.
        • Blesso C.N.
        Dietary and endogenous sphingolipid metabolism in chronic inflammation.
        Nutrients. 2017; 9: 1180
        • Edsfeldt A.
        • Dunér P.
        • Ståhlman M.
        • Mollet I.G.
        • Asciutto G.
        • Grufman H.
        • Nitulescu M.
        • Persson A.F.
        • Fisher R.M.
        • Melander O.
        Sphingolipids contribute to human atherosclerotic plaque inflammation.
        Arteriosclerosis, thrombosis, and vascular biology. 2016; 36: 1132-1140
        • Gupta G.
        • Baumlin N.
        • Poon J.
        • Ahmed B.
        • Chiang Y.-P.
        • Railwah C.
        • Kim M.D.
        • Rivas M.
        • Goldenberg H.
        • Elgamal Z.
        Airway resistance caused by sphingomyelin synthase 2 insufficiency in response to cigarette smoke.
        American journal of respiratory cell and molecular biology. 2020; 62: 342-353
        • Bowler R.P.
        • Jacobson S.
        • Cruickshank C.
        • Hughes G.J.
        • Siska C.
        • Ory D.S.
        • Petrache I.
        • Schaffer J.E.
        • Reisdorph N.
        • Kechris K.
        Plasma sphingolipids associated with chronic obstructive pulmonary disease phenotypes.
        American journal of respiratory and critical care medicine. 2015; 191: 275-284
        • Khayrullin A.
        • Krishnan P.
        • Martinez-Nater L.
        • Mendhe B.
        • Fulzele S.
        • Liu Y.
        • Mattison J.A.
        • Hamrick M.W.
        Very long-chain C24: 1 ceramide is increased in serum extracellular vesicles with aging and can induce senescence in bone-derived mesenchymal stem cells.
        Cells. 2019; 8: 37
        • Park S.W.
        • Kim M.
        • Chen S.W.
        • Brown K.M.
        • D D'Agati V.
        • Lee H.T.
        Sphinganine-1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in mice through S1P 1 receptor activation.
        Laboratory investigation. 2010; 90: 1209-1224
        • Nagata M.
        • Izumi Y.
        • Ishikawa E.
        • Kiyotake R.
        • Doi R.
        • Iwai S.
        • Omahdi Z.
        • Yamaji T.
        • Miyamoto T.
        • Bamba T.
        Intracellular metabolite β-glucosylceramide is an endogenous Mincle ligand possessing immunostimulatory activity.
        Proceedings of the National Academy of Sciences. 2017; 114: E3285-E3294
        • Jeong Y.-H.
        • Kim Y.
        • Song H.
        • Chung Y.S.
        • Park S.B.
        • Kim H.-S.
        Anti-inflammatory effects of α-galactosylceramide analogs in activated microglia: involvement of the p38 MAPK signaling pathway.
        PLoS One. 2014; 9
        • von Gerichten J.
        • Lamprecht D.
        • Opálka L.
        • Soulard D.
        • Marsching C.
        • Pilz R.
        • Sencio V.
        • Herzer S.
        • Galy B.
        • Nordström V.
        Bacterial immunogenic α-galactosylceramide identified in the murine large intestine: dependency on diet and inflammation.
        J Lipid Res. 2019; 60: 1892-1904
        • Apostolopoulou M.
        • Gordillo R.
        • Koliaki C.
        • Gancheva S.
        • Jelenik T.
        • De Filippo E.
        • Herder C.
        • Markgraf D.
        • Jankowiak F.
        • Esposito I.
        Specific hepatic sphingolipids relate to insulin resistance, oxidative stress, and inflammation in nonalcoholic steatohepatitis.
        Diabetes Care. 2018; 41: 1235-1243
        • Zhang J.-Y.
        • Qu F.
        • Li J.-F.
        • Liu M.
        • Ren F.
        • Zhang J.-Y.
        • Bian D.-D.
        • Chen Y.
        • Duan Z.-P.
        • Zhang J.-L.
        Up-regulation of plasma hexosylceramide (d18: 1/18: 1) contributes to genotype 2 virus replication in chronic hepatitis C: A 20-year cohort study.
        Medicine. 2016; 23
        • Jang H.J.
        • Lim S.
        • Kim J.M.
        • Yoon S.
        • Lee C.Y.
        • Hwang H.J.
        • Shin J.W.
        • Shin K.J.
        • Kim H.Y.
        • Park K.I.
        Glucosylceramide synthase regulates adipo-osteogenic differentiation through synergistic activation of PPARγ with GlcCer.
        The FASEB Journal. 2020; 34: 1270-1287
        • Murugesan V.
        • Chuang W.L.
        • Liu J.
        • Lischuk A.
        • Kacena K.
        • Lin H.
        • Pastores G.M.
        • Yang R.
        • Keutzer J.
        • Zhang K.
        Glucosylsphingosine is a key biomarker of Gaucher disease.
        American journal of hematology. 2016; 91: 1082-1089
        • Sun J.M.
        • Dawson G.
        • Franz L.
        • Howard J.
        • McLaughlin C.
        • Kistler B.
        • Waters-Pick B.
        • Meadows N.
        • Troy J.
        • Kurtzberg J.
        Infusion of human umbilical cord tissue mesenchymal stromal cells in children with autism spectrum disorder.
        Stem Cells Transl Med. 2020; 9: 1137-1146
        • Shaner R.L.
        • Allegood J.C.
        • Park H.
        • Wang E.
        • Kelly S.
        • Haynes C.A.
        • Sullards M.C.
        • Merrill Jr., A.H.
        Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers.
        J Lipid Res. 2009; 50: 1692-1707
      View full text