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Manufacturing mesenchymal stromal cells for phase I clinical trials

      Abstract

      Mesenchymal stromal cells (MSCs) are multipotent progenitor cells capable of differentiating into adipocytes, osteoblasts and chondroblasts as well as secreting a vast array of soluble mediators. This potentially makes MSCs important mediators of a variety of therapeutic applications. They are actively under evaluation for immunomodulatory purposes such as graft-versus-host disease and Crohn’s disease as well as regenerative applications such as stroke and congestive heart failure. We report our method of generating clinical-grade MSCs together with suggestions gathered from manufacturing experience in our Good Manufacturing Practices facility.

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      References

        • Friedenstein A.J.
        • Deriglasova U.F.
        • Kulagina N.N.
        • Panasuk A.F.
        • Rudakowa S.F.
        • Luria E.A.
        • et al.
        Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method.
        Exp Hematol. 1974; 2: 83-92
        • Pittenger M.F.
        • Mackay A.M.
        • Beck S.C.
        • Jaiswal R.K.
        • Douglas R.
        • Mosca J.D.
        • et al.
        Multilineage potential of adult human mesenchymal stem cells.
        Science. 1999; 284: 143-147
        • Caplan A.I.
        Mesenchymal stem cells.
        J Orthop Res. 1991; 9: 641-650
        • Fossett E.
        • Khan W.S.
        Optimising human mesenchymal stem cell numbers for clinical application: a literature review.
        Stem Cells Int. 2012; 2012: 465259
        • D'Ippolito G.
        • Schiller P.C.
        • Ricordi C.
        • Roos B.A.
        • Howard G.A.
        Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow.
        J Bone Miner Res. 1999; 14: 1115-1122
        • Malgieri A.
        • Kantzari E.
        • Patrizi M.P.
        • Gambardella S.
        Bone marrow and umbilical cord blood human mesenchymal stem cells: state of the art.
        Int J Clin Exp Med. 2010; 3: 248-269
        • Campagnoli C.
        • Roberts I.A.
        • Kumar S.
        • Bennett P.R.
        • Bellantuono I.
        • Fisk N.M.
        Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow.
        Blood. 2001; 98: 2396-2402
        • Gotherstrom C.
        • Ringden O.
        • Westgren M.
        • Tammik C.
        • Le B.K.
        Immunomodulatory effects of human foetal liver-derived mesenchymal stem cells.
        Bone Marrow Transplant. 2003; 32: 265-272
        • Nauta A.J.
        • Fibbe W.E.
        Immunomodulatory properties of mesenchymal stromal cells.
        Blood. 2007; 110: 3499-3506
        • Sensebe L.
        • Bourin P.
        • Tarte K.
        Good manufacturing practices production of mesenchymal stem/stromal cells.
        Hum Gene Ther. 2011; 22: 19-26
        • Bieback K.
        • Kinzebach S.
        • Karagianni M.
        Translating research into clinical scale manufacturing of mesenchymal stromal cells.
        Stem Cells Int. 2011; 2010: 193519
        • Vidal M.A.
        • Walker N.J.
        • Napoli E.
        • Borjesson D.L.
        Evaluation of senescence in mesenchymal stem cells isolated from equine bone marrow, adipose tissue, and umbilical cord tissue.
        Stem Cells Dev. 2012; 21: 273-283
        • Muller I.
        • Kordowich S.
        • Holzwarth C.
        • Spano C.
        • Isensee G.
        • Staiber A.
        • et al.
        Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM.
        Cytotherapy. 2006; 8: 437-444
        • Horwitz E.M.
        • Gordon P.L.
        • Koo W.K.
        • Marx J.C.
        • Neel M.D.
        • McNall R.Y.
        • et al.
        Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone.
        Proc Natl Acad Sci U S A. 2002; 99: 8932-8937
        • Horwitz E.M.
        • Prockop D.J.
        • Fitzpatrick L.A.
        • Koo W.W.
        • Gordon P.L.
        • Neel M.
        • et al.
        Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta.
        Nat Med. 1999; 5: 309-313
        • Krampera M.
        • Glennie S.
        • Dyson J.
        • Scott D.
        • Laylor R.
        • Simpson E.
        • et al.
        Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide.
        Blood. 2003; 101: 3722-3729
        • Dominici M.
        • Le B.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: 315-317
        • Pytlik R.
        • Stehlik D.
        • Soukup T.
        • Kalbacova M.
        • Rypacek F.
        • Trc T.
        • et al.
        The cultivation of human multipotent mesenchymal stromal cells in clinical grade medium for bone tissue engineering.
        Biomaterials. 2009; 30: 3415-3427
        • Philippe B.
        • Luc S.
        • Valerie P.B.
        • Jerome R.
        • Alessandra B.R.
        • Louis C.
        Culture and use of mesenchymal stromal cells in phase I and II clinical trials.
        Stem Cells Int. 2010; 2010: 503593
        • Abumaree M.
        • Al J.M.
        • Pace R.A.
        • Kalionis B.
        Immunosuppressive properties of mesenchymal stem cells.
        Stem Cell Rev. 2012; 8: 375-392
        • Tu Z.
        • Li Q.
        • Bu H.
        • Lin F.
        Mesenchymal stem cells inhibit complement activation by secreting factor H.
        Stem Cells Dev. 2010; 19: 1803-1809
        • Newman R.E.
        • Yoo D.
        • LeRoux M.A.
        • Danilkovitch-Miagkova A.
        Treatment of inflammatory diseases with mesenchymal stem cells.
        Inflamm Allergy Drug Targets. 2009; 8: 110-123
        • Tarte K.
        • Gaillard J.
        • Lataillade J.J.
        • Fouillard L.
        • Becker M.
        • Mossafa H.
        • et al.
        Clinical-grade production of human mesenchymal stromal cells: occurrence of aneuploidy without transformation.
        Blood. 2010; 115: 1549-1553
        • Battula V.L.
        • Treml S.
        • Bareiss P.M.
        • Gieseke F.
        • Roelofs H.
        • de Zwart P.
        • et al.
        Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1.
        Haematologica. 2009; 94: 173-184
        • Wagner S.J.
        • Myrup A.C.
        Toward closed-system culture of blood origin endothelial cells.
        Transfusion. 2005; 45: 1201-1207
        • Kedong S.
        • Xiubo F.
        • Tianqing L.
        • Macedo H.M.
        • LiLi J.
        • Meiyun F.
        • et al.
        Simultaneous expansion and harvest of hematopoietic stem cells and mesenchymal stem cells derived from umbilical cord blood.
        J Mater Sci Mater Med. 2010; 21: 3183-3193
        • Nguyen K.
        • McNiece I.
        • Antwiler D.
        Reproducible growth and expansion of bone marrow derived mesenchymal stem cells (MSC), using a novel, automated and closed cell expansion system (CES) [abstract].
        Cytotherapy. 2008; 10