{"doi":"10.1016/j.bbmt.2020.02.023","title":"Mesenchymal Stromal Cells for Graft-versus-Host Disease: A Trilogy","abstract":"This issue of the journal showcases 3 clinical trials [1Kebriaei P. Hayes J. Daly A. et al.A phase 3 randomized study of remestemcel-l versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 835-844Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 2Kurtzberg J. Prockop S. Chaudhury S. et al.Study 275: updated expanded access program for remestemcel-l in steroid-refractory acute graft-versus-host disease in children.Biol Blood Marrow Transplant. 2020; 26: 855-864Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 3Kurtzberg J. Abdel-Azim H. Carpenter P. et al.A phase 3, single-arm, prospective study of remestemcel-l, ex vivo culture-expanded adult human mesenchymal stromal cells for the treatment of pediatric patients who failed to respond to steroid treatment for acute graft-versus-host disease.Biol Blood Marrow Transplant. 2020; 26: 845-854Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], each focused on testing the utility of industrially sourced culture-adapted allogeneic mesenchymal stromal cells (MSCs; remestemcel-L) as a transfusion product to improve the outcome of steroid-refractory acute graft-versus-host disease (GHVD). Culture-adapted bone marrow (BM)-derived MSCs compose a polyclonal population of stromal cells with regenerative and immunomodulatory properties that buttress their clinical study as cellular pharmaceuticals [4Galipeau J. Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities.Cell Stem Cell. 2018; 22: 824-833Abstract Full Text Full Text PDF PubMed Scopus (848) Google Scholar]. These culture-adapted MSCs will replicate vigorously in vitro as long as they are maintained in serum and display robust, predominantly paracrine anti-inflammatory, angiogenic, and bystander regenerative cell physiological properties [5Ferreira J.R. Teixeira G.Q. Santos S.G. Barbosa M.A. Almeida-Porada G. Gonçalves R.M. Mesenchymal stromal cell secretome: influencing therapeutic potential by cellular pre-conditioning.Front Immunol. 2018; 9: 2837Crossref PubMed Scopus (255) Google Scholar]. These effects arise from a matrix of cell physiological interactions involving a spectrum of small molecules, peptides, chemokines, cytokines, morphogens, and exosomes, reflecting in part their tissue endogenous role as marrow niche cells [6Wang Y Chen X. Cao W. Shi Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications.Nat Immunol. 2014; 15: 1009-1016Crossref PubMed Scopus (921) Google Scholar]. The translational human use of BM-MSCs as a cellular pharmaceutical was inaugurated in 1995 with the first published clinical trial of i.v. BM-MSCs in the setting of autologous peripheral hematopoietic stem cell transplantation (HSCT) with the aim of accelerating hematopoietic recovery [7Lazarus H.M. Haynesworth S.E. Gerson S.L. Rosenthal N.S. Caplan A.I. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use.Bone Marrow Transplant. 1995; 16: 557-564PubMed Google Scholar]. The discovery of MSCs' ability to profoundly affect the functionality of bystander innate and adaptive immune cells [8Bernardo M.E. Fibbe W.E. Mesenchymal stromal cells: sensors and switchers of inflammation.Cell Stem Cell. 2013; 13: 392-402Abstract Full Text Full Text PDF PubMed Scopus (948) Google Scholar] and this biological feature plausibly allowed reversal of steroid resistant acute GVHD, as first described in a case report and later validated in a well-designed phase II European trial [9Le Blanc K. Frassoni F. Ball L. et al.Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.Lancet. 2008; 371: 1579-1586Abstract Full Text Full Text PDF PubMed Scopus (2183) Google Scholar]. 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