The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter II: Emerging transformational cytotherapies

Regenerative Medicine

Volumn 10, Issue 3, 2015, Pages 345-373

  Vertès, Alain A ^a,b  

^a LONDON BUSINESS SCHOOL   (United Kingdom)

^b NxR Biotechnologies GmbH   (Switzerland)

Author keywords

graft versus host disease; GvHD; hematopoietic stem cells; mesenchymal stem cells; NK cells; transplantation; Tregs

Indexed keywords

16,16 DIMETHYLPROSTAGLANDIN E2; ANTIFUNGAL AGENT; CD34 ANTIGEN; CHEMOKINE RECEPTOR CXCR4; CORTICOSTEROID; DIPEPTIDYL PEPTIDASE IV; GRANULOCYTE COLONY STIMULATING FACTOR; SITAGLIPTIN; STEM CELL FACTOR; STROMAL CELL DERIVED FACTOR 1; BIOLOGICAL MARKER;

ACUTE GRAFT VERSUS HOST DISEASE; CD34 SELECTION; CELL THERAPY; CHRONIC GRAFT VERSUS HOST DISEASE; CORD BLOOD STEM CELL TRANSPLANTATION; EMBRYONIC STEM CELL; ENGRAFTMENT; FEEDER CELL; GRAFT FAILURE; GRAFT VERSUS HOST REACTION; HEMATOLOGIC MALIGNANCY; HEMATOPOIETIC STEM CELL; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HLA MATCHING; HUMAN; IMMUNOGENICITY; IMMUNOMODULATION; LYMPHOCYTE HOMING; MESENCHYMAL STEM CELL; NATURAL KILLER CELL; NON INSULIN DEPENDENT DIABETES MELLITUS; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; STEM CELL EXPANSION; ANEMIA; ANIMAL; BIOLOGICAL THERAPY; CONVALESCENCE; GRAFT VS HOST DISEASE; HEMATOLOGIC NEOPLASMS; HEMATOPOIESIS; IMMUNOLOGIC DEFICIENCY SYNDROMES; IMMUNOLOGY; MORTALITY; PROCEDURES; REGENERATIVE MEDICINE; TRENDS;

ANEMIA; ANIMALS; BIOMARKERS; CELL- AND TISSUE-BASED THERAPY; GRAFT VS HOST DISEASE; HEMATOLOGIC NEOPLASMS; HEMATOPOIESIS; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMANS; IMMUNOLOGIC DEFICIENCY SYNDROMES; RECOVERY OF FUNCTION; REGENERATIVE MEDICINE;

EID: 84930000273     PISSN: 17460751     EISSN: 1746076X     Source Type: Journal    
DOI: 10.2217/rme.15.13     Document Type: Review

References (279)

1. Vertes AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: Current practice and remaining unmet medical needs. Regen. Med. 10 (3), 331-373 (2015) (In Press).
2. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N. Engl. J. Med. 257(11), 491-496 (1957).
3. Thomas ED, Fefer A, Buckner CD, Storb R. Current status of blood marrow transplantation for aplastic anemia and acute leukemia. Blood 49(5), 671-681 (1977).
4. Storb R, Thomas ED, Weiden PL et al. Aplastic anemia treated by allogeneic blood marrow transplantation: a report on 49 new cases from Seattle. Blood 48(6), 817-841 (1976).
5. Jenq RR, Van den Brink MR. Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat. Rev. Cancer 10(3), 213-221 (2010).
6. Gratwohl A, Baldomero H, Horisberger B, Schmid C, Passweg J, Urbano-Ispizua A. Current trends in hematopoietic stem cell transplantation in Europe. Blood 100(7), 2374-2386 (2002).
7. Appelbaum FR. Hematopoietic-cell transplantation at 50. N. Engl. J. Med. 357, 1472-1475 (2007).
8. Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112(12), 4371-4383 (2008).
9. Barton-Burke M, Dwinell DM, Kafkas L et al. Graft-versushost disease: a complex long-Term side effect of hematopoietic stem cell transplant. Oncology (Williston Park) 22(11 Suppl. Nurse Ed.), 31-45 (2008).
10. Sung AD, Chao NJ. Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment. Stem Cells Transl. Med. 2(1), 25-32 (2013).
11. Teshima T. Th1 and Th17 join forces for acute GvHD. Blood 118(18), 4765-4767 (2011).
12. Pan B, Zhang Y, Sun Y et al. Deviated balance between Th1 and Th17 cells exacerbates acute graft-versus-host disease in mice. Cytokine 68(2), 69-75 (2014).
13. Coghill JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR, Serody JS. Effector CD4+ T cells, the cytokines they generate, and GvHD: something old and something new. Blood 117(12), 3268-3276 (2011).
14. Harris AC, Ferrara JL, Braun TM et al. Plasma biomarkers of lower gastrointestinal and liver acute GVHD. Blood 119(12), 2960-2963 (2012).
15. Macmillan ML, Defor TE, Weisdorf DJ. The best endpoint for acute GVHD treatment trials. Blood 115(26), 5412-5417 (2010).
16. Vertes AA. Deciphering the therapeutic stem cell strategies of large and midsize pharmaceutical firms. Regen. Med. 9(4), 479-495 (2014).
17. Vertes AA, Qureshi N, Caplan AI, Babiss L. Stem Cells in Regenerative Medicine: Science, Regulation, and Business Strategies. Wiley, Chichester, UK (2015).
18. Sharma RR, Pollock K, Hubel A, Mckenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 54(5), 1418-1437 (2014).
19. Thirumala S, Goebel WS, Woods EJ. Manufacturing and banking of mesenchymal stem cells. Expert Opin. Biol. Ther. 13(5), 673-691 (2013).
20. Francois M, Copland IB, Yuan S, Romieu-Mourez R, Waller EK, Galipeau J. Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing. Cytotherapy 14(2), 147-152 (2012).
21. Galipeau J. Concerns arising from MSC retrieval from cryostorage and effect on immune suppressive function and pharmaceutical usage in clinical trials. ISBT Sci. Series 8(1), 100-101 (2013).
22. Qasim W, Thrasher AJ. Progress and prospects for engineered T-cell therapies. Br. J. Haematol. 166(6), 818-829 (2014).
23. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13(4), 392-402 (2013).
24. Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Annu. Rev. Pathol. 6, 457-478 (2011).
25. Metheny L, Caimi P, De Lima M. Cord blood transplantation: can we make it better? Front. Oncol. 3, 238 (2013).
26. Battiwalla M, Barrett AJ. Bone marrow mesenchymal stromal cells to treat complications following allogeneic stem cell transplantation. Tissue Eng. Part B Rev. 20(3), 211-217 (2014).
27. Amorin B, Alegretti AP, Valim V et al. Mesenchymal stem cell therapy and acute graft-versus-host disease: a review. Hum. Cell 27(4), 137-150 (2014).
28. Ringden O, Uzunel M, Rasmusson I et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10), 1390-1397 (2006).
29. Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8(4), 315-317 (2006).
30. English K, Mahon BP. Allogeneic mesenchymal stem cells: agents of immune modulation. J. Cell. Biochem. 112(8), 1963-1968 (2011).
31. James AA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 32(3), 252-260 (2014).
32. Lalu MM, Mcintyre L, Pugliese C et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-Analysis of clinical trials. PLoS One 7(10), e47559 (2012).
33. Devine SM, Bartholomew AM, Mahmud N et al. Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp. Hematol. 29(2), 244-255 (2001).
34. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 32(3), 252-260 (2014).
35. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EG, Willemze R, Fibbe WE. Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108(6), 2114-2120 (2006).
36. Mukonoweshuro B. Immunogenicity of Allogeneic Mouse Mesenchymal Stem Cells (MSC) [PhD thesis]. Faculty of Biological Sciences PhD The University of Leeds, UK (2012).
37. Vertes AA. Creating an effective delivery plan for cell therapy. In: World Stem Cell Report 2009. Siegel B, Margolin RE, Blatt RJ, Haecker S (Eds). Genetics Policy Institute, Palm Beach, FA, USA (2009).
38. Campeau PM, Rafei M, Francois M, Birman E, Forner KA, Galipeau J. Mesenchymal stromal cells engineered to express erythropoietin induce anti-erythropoietin antibodies and anemia in allorecipients. Mol. Ther. 17(2), 369-372 (2009).
39. Trounson A, Thakar RG, Lomax G, Gibbons D. Clinical trials for stem cell therapies. BMC Med. 9, 52 (2011).
40. Komanduri KV, St John LS, de Lima M et al. Delayed immune reconstitution after cord blood transplantation is characterized by impaired thymopoiesis and late memory T-cell skewing. Blood 110(13), 4543-4551 (2007).
41. Ballen KK, Gluckman E, Broxmeyer HE. Umbilical cord blood transplantation: the first 25 years and beyond. Blood 122(4), 491-498 (2013).
42. Taupin P. Transplantation of cord blood stem cells for treating hematologic diseases and strategies to improve engraftment. Regen. Med. 7(6), 703-715 (2010).
43. Danby R, Rocha V. Current strategies to improve engraftment in cord blood transplantation. J. Stem Cell Res. Ther. 4(2), 172 (2014).
44. Barker JN, Fei M, Karanes C et al. Results of a prospective multicentre myeloablative double-unit cord blood transplantation trial in adult patients with acute leukaemia and myelodysplasia. Br. J. Haematol. 168(3), 405-412 (2014).
45. Barker JN, Weisdorf DJ, Defor TE et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 105(3), 1343-1347 (2005).
46. Scaradavou A, Brunstein CG, Eapen M et al. Double unit grafts successfully extend the application of umbilical cord blood transplantation in adults with acute leukemia. Blood 121(5), 752-758 (2013).
47. Schmitz N, Beksac M, Hasenclever D et al. Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia. Blood 100(3), 761-767 (2002).
48. Horowitz MM, Rowlings PA, Passweg JR. Allogeneic blood marrow transplantation for CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow Transplant. 17(Suppl. 3), S5-S6 (1996).
49. Lau TT, Wang DA. Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine. Expert Opin. Biol. Ther. 11(2), 189-197 (2011).
50. Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair. Gene Ther. 19(6), 583-587 (2012).
51. Brenner S, Whiting-Theobald N, Kawai T et al. Transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells. Stem Cells 22(7), 1128-1133 (2004).
52. Wynn RF, Hart CA, Corradi-Perini C et al. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood 104(9), 2643-2645 (2004).
53. Ramirez P, Wagner JE, Defor TE et al. CXCR4 expression in CD34+ cells and unit predominance after double umbilical cord blood transplantation. Leukemia 27(5), 1181-1183 (2013).
54. Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood 106(6), 1901-1910 (2005).
55. Berg EL, Mcevoy LM, Berlin C, Bargatze RF, Butcher EC. L-selectin-mediated lymphocyte rolling on MAdCAM-1. Nature 366(6456), 695-698 (1993).
56. Somers WS, Tang J, Shaw GD, Camphausen RT. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P-And E-selectin bound to SLeX and PSGL-1. Cell 103, 467-479 (2000).
57. Frenette PS, Subbarao S, Mazo IB, Von Andrian UH, Wagner DD. Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. Proc. Natl Acad. Sci. USA 95(24), 14423-14428 (1998).
58. Katayama Y, Hidalgo A, Furie BC, Vestweber D, Furie B, Frenette PS. PSGL-1 participates in E-selectin mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and alpha4 integrin. Blood 102(6), 2060-2067 (2003).
59. Mazo IB, Gutierrez-Ramos JC, Frenette PS, Hynes RO, Wagner DD, von Andrian UH. Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1. J. Exp. Med. 188(3), 465-474 (1998).
60. Robinson SN, Thomas MW, Lu JJ et al. Cord blood CD34+ stem cell Sialyl Lewis X levels and E-selectin binding are predictive of engraftment in mice: functional separation of stemness and homing to improve engraftment. Blood 122(21), 893 (2013).
61. Jubeli E, Moine L, Vergnaud-Gauduchon J, Barratt G. E-selectin as a target for drug delivery and molecular imaging. J Control. Release 158(2), 194-206 (2012).
62. Luhn K, Wild MK. Human deficiencies of fucosylation and sialylation affecting selectin ligands. Semin. Immunopathol. 34(3), 383-399 (2012).
63. Robinson SN, Simmons PJ, Thomas MW et al. Ex vivo fucosylation improves human cord blood engraftment in NOD-SCID IL-2Rgamma(null) mice. Exp. Hematol. 40(6), 445-456 (2012).
64. Xia L, Mcdaniel JM, Yago T, Doeden A, Mcever RP. Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow. Blood 104(10), 3091-3096 (2004).
65. ClinicalTrial Database: NCT01471067. https://clinicaltrials.gov/ct2/show/NCT01471067
66. ClinicalTrial Database: NCT01983761. https://clinicaltrials.gov/ct2/show/NCT01983761
67. Robinson SN, Thomas MW, Simmons PJ et al. Fucosylation with fucosyltransferase VI or fucosyltransferase VII improves cord blood engraftment. Cytotherapy 16(1), 84-89 (2014).
68. Popat UR, Oran B, Hosing CM et al. Ex vivo fucosylation of cord blood accelerates neutrophil and platelet engraftment. Blood 122, 691 (2013).
69. Farag SS, Srivastava S, Messina-Graham S et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 22(7), 1007-1015 (2013).
70. O'leary H, Ou X, Broxmeyer HE. The role of dipeptidyl peptidase 4 in hematopoiesis and transplantation. Curr. Opin. Hematol. 20(4), 314-319 (2013).
71. Li L, Kim HT, Nellore A et al. Prostaglandin E2 promotes survival of naive UCB T-cells via the Wnt/beta-catenin pathway and alters immune reconstitution after UCBT. Blood Cancer J. 4, e178 (2014).
72. Cutler C, Multani P, Robbins D et al. Prostaglandinmodulated umbilical cord blood hematopoietic stem cell transplantation. Blood 122(17), 3074-3081 (2013).
73. Goessling W, Allen RS, Guan X et al. Prostaglandin E2 enhances engraftment of human cord blood stem cells and shows long-Term safety in preclinical non-human primate transplant models. Cell Stem Cell 8, 445-458 (2011).
74. ClinicalTrial Database: NCT00862719. https://clinicaltrials.gov/ct2/show/NCT00862719
75. De Mendizábal NV, Strother RM, Farag SS et al. Modelling the sitagliptin effect on dipeptidyl peptidase-4 activity in adults with haematological malignancies after umbilical cord blood haematopoietic cell transplantation. Clin. Pharmacokinet. 53(3), 247-259 (2014).
76. ClinicalTrial Database: NCT01720264. https://clinicaltrials.gov/ct2/show/NCT01720264
77. Hal BE, Pelus LM. Inhibition of DPP4/CD26 and dmPGE treatment enhances engraftment of mouse bone marrow hematopoietic stem cells. Blood Cells Mol. Dis. 53(1), 34-38 (2014).
78. ClinicalTrial Database: NCT01527838. https://clinicaltrials.gov/ct2/show/NCT01527838
79. Beksac M, Yurdakul P. Modalities to improve cord blood engraftment. J. Stem Cell Res. Ther. 4(3), 182 (2014).
80. Sastry PS. Ex vivo expanded allogeneic cord blood progenitor cell transplantation with a non-myeloablative conditioning regimen would cure autoimmune diseases. Med. Hypotheses 54(3), 423-424 (2000).
81. Shpall EJ, Quinones R, Giller R et al. Transplantation of ex vivo expanded cord blood. Biol. Blood Marrow Transplant. 8(7), 368-376 (2002).
82. Bordeaux-Rego P, Luzo A, Costa FF, Olalla Saad ST, Crosara-Alberto DP. Both interleukin-3 and interleukin-6 are necessary for better ex vivo expansion of CD133+ cells from umbilical cord blood. Stem Cell Dev. 19, 413-422 (2010).
83. Dahlberg A, Delaney C, Bernstein ID. Ex vivo expansion of human hematopoietic stem and progenitor cells. Blood 117(23), 6083-6090 (2011).
84. De Lima M, Mcniece I, Robinson SN et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N. Engl. J. Med. 367(24), 2305-2315 (2012).
85. Gratwohl A, Baldomero H, Aljurf M et al. Hematopoietic stem cell transplantation: a global perspective. JAMA 303(16), 1617-1624 (2010).
86. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat. Med. 16(2), 232-236 (2010).
87. De Lima M, Mcmannis J, Gee A et al. Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Blood Marrow Transplant. 41(9), 771-778 (2008).
88. Peled T, Glukhman E, Hasson N et al. Chelatable cellular copper modulates differentiation and self-renewal of cord blood-derived hematopoietic progenitor cells. Exp. Hematol. 33(10), 1092-1100 (2005).
89. Stiff PJ, Montesinos P, Peled T et al. StemEx® (copper chelation based) ex vivo expanded umbilical cord blood stem cell transplantation (UCBT) accelerates engraftment and improves 100 day survival in myeloablated patients compared to a registry cohort undergoing double unit UCBT: results of a multicenter study of 101 patients with hematologic malignancies. Blood 122, 295 (2013).
90. Carroll J. Novartis slashes ante, inks another Gamida Cell buyout pact in $635M leukemia deal Fierce Biotech, 19 August (2014).
91. ClinicalTrial Datase: NCT00469729. https://clinicaltrials.gov/ct2/show/NCT00469729
92. Gamida cell reports FDA recommending further study of StemEx. Gamida Cell, www.gamida-cell.com/press-item.asp?id=56
93. Horwitz ME, Chao NJ, Rizzieri DA et al. Umbilical cord blood expansion with nicotinamide provides long-Term multilineage engraftment. J. Clin. Invest. 124(7), 3121-3128 (2014).
94. ClinicalTrial Database: NCT01221857. https://clinicaltrials.gov/ct2/show/NCT01221857
95. Boitano AE, Wang J, Romeo R et al. Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329(5997), 1345-1348 (2010).
96. ClinicalTrial Database: NCT01474681. https://clinicaltrials.gov/ct2/show/NCT01474681
97. Wagner JE, Brunstein CG, Mckenna D et al. Safety and exploratory efficacy of ex vivo expanded umbilical cord blood (UCB) hematopoietic stem and progenitor cells (HSPC) using cytokines and Stem-Regenin 1 (SR1): interim results of a phase 1/2 dose escalation clinical study. Blood 122(21), 698 (2013).
98. ClinicalTrial Database: NCT01930162. https://clinicaltrials.gov/ct2/show/NCT01930162
99. Gori JL, Watts KL, Chandrasekaran D, Sauvageau G, Kiem HP. Effective expansion and engraftment of nonhuman primate CD34+ hematopoietic stem cells after co-culture with the small molecule UM171. Blood 122(21), 1656 (2013).
100. Li W, Li K, Wei W, Ding S. Chemical approaches to stem cell biology and therapeutics. Cell Stem Cell 13(3), 270-283 (2013).
101. Yoder MC. Cord blood banking and transplantation: advances and controversies. Curr. Opin. Pediatr. 26(2), 163-168 (2014).
102. Xu T, Zhang M, Laurent T, Xie M, Ding S. Concise review: chemical approaches for modulating lineage-specific stem cells and progenitors. Stem Cells Transl. Med. 2(5), 355-361 (2013).
103. Fares I, Chagraoui J, Gareau Y et al. UM171 is a novel and potent agonist of human hematopoietic stem cell renewal. Blood 122(21), 798 (2013).
104. Walenda T, Bokermann G, Ventura Ferreira MS et al. Synergistic effects of growth factors and mesenchymal stromal cells for expansion of hematopoietic stem and progenitor cells. Exp. Hematol. 39(6), 617-628 (2011).
105. Mehrasa R, Vaziri H, Oodi A et al. Mesenchymal stem cells as a feeder layer can prevent apoptosis of expanded hematopoietic stem cells derived from cord blood. Int. J. Mol. Cell. Med. 3(1), 1-10 (2014).
106. Perdomo-Arciniegas AM, Vernot JP. Co-culture of hematopoietic stem cells with mesenchymal stem cells increases VCAM-1-dependent migration of primitive hematopoietic stem cells. Int. J. Hematol. 94(6), 525-532 (2011).
107. Fong CY, Gauthaman K, Cheyyatraivendran S, Lin HD, Biswas A, Bongso A. Human umbilical cord Wharton's jelly stem cells and its conditioned medium support hematopoietic stem cell expansion ex vivo. J. Cell. Biochem. 113(2), 658-668 (2012).
108. Jing D, Fonseca AV, Alakel N et al. Hematopoietic stem cells in co-culture with mesenchymal stromal cells-modeling the niche compartments in vitro. Haematologica 95(4), 542-550 (2010).
109. Walenda T, Bork S, Horn P et al. Co-culture with mesenchymal stromal cells increases proliferation and maintenance of haematopoietic progenitor cells. J. Cell. Mol. Med. 14(1-2), 337-350 (2010).
110. Fei XM, Wu YJ, Chang Z et al. Co-culture of cord blood CD34(+) cells with human BM mesenchymal stromal cells enhances short-Term engraftment of cord blood cells in NOD/SCID mice. Cytotherapy 9(4), 338-347 (2007).
111. Battiwalla M, Hematti P. Mesenchymal stem cells in hematopoietic stem cell transplantation. Cytotherapy 11(5), 503-515 (2009).
112. Kelly SS, Sola CB, de Lima M, Shpall E. Ex vivo expansion of cord blood. Blood Marrow Transplant. 44(10), 673-681 (2009).
113. Cook MM. Mesenchymal stem cells and haematopoietic stem cell culture. In: Mesenchymal Stem Cell Therapy. Chase LG, Bvemuri MC (Eds). Humana Press, New York, NY, USA, 161-172 (2013).
114. ClinicalTrial Database: NCT01854567 https://clinicaltrials.gov/ct2/show/NCT01854567
115. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res. Ther. 9(1), 204 (2007).
116. Psaltis PJ, Paton S, See F et al. Enrichment for STRO-1 expression enhances the cardiovascular paracrine activity of human bone marrow-derived mesenchymal cell populations. J. Cell. Physiol. 223(2), 530-540 (2010).
117. Harichandan A, Buhring HJ. Prospective isolation of human MSC. Best Pract. Res. Clin. Haematol. 24(1), 25-36 (2011).
118. ClinicalTrial Database: NCT00498316. https://clinicaltrials.gov/ct2/show/NCT00498316
119. Le Blanc K, Samuelsson H, Gustafsson B et al. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells. Leukemia 21(8), 1733-1738 (2007).
120. Ball LM, Bernardo ME, Roelofs H et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 110(7), 2764-2767 (2007).
121. Carrancio S, Romo C, Ramos T et al. Effects of MSC coadministration and route of delivery on cord blood hematopoietic stem cell engraftment. Cell Transplant. 22(7), 1171-1183 (2013).
122. Koc ON, Gerson SL, Cooper BW et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J. Clin. Oncol. 18(2), 307-316 (2000).
123. Lazarus HM, Koc ON, Devine SM et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol. Blood Marrow Transplant. 11(5), 389-398 (2005).
124. Macmillan ML, Blazar BR, Defor TE, Wagner JE. Transplantation of ex-vivo culture-expanded parental haploidentical mesenchymal stem cells to promote engraftment in pediatric recipients of unrelated donor umbilical cord blood: results of a Phase I-II clinical trial. Blood Marrow Transplant. 43(6), 447-454 (2009).
125. Bernardo ME, Ball LM, Cometa AM et al. Co-infusion of ex vivo-expanded, parental MSCs prevents life-Threatening acute GVHD, but does not reduce the risk of graft failure in pediatric patients undergoing allogeneic umbilical cord blood transplantation. Blood Marrow Transplant. 46(2), 200-207 (2011).
126. ClinicalTrial Database: NCT01045382 https://clinicaltrials.gov/ct2/show/NCT01045382
127. ClinicalTrial Database: NCT01092026 https://clinicaltrials.gov/ct2/show/NCT01092026
128. ClinicalTrial Database: NCT02181478. https://clinicaltrials.gov/ct2/show/NCT02181478
129. Yang NH, Jiang F, Hu M et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 22, 593-599 (2008).
130. Behre G, Theurich S, Weber T, Christopeit M Reply to 'The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rates in hematologic malignancy patients: outcome of a pilot clinical study' by Ning et al. Leukemia 23, 178-214 (2009).
131. Ning H, Yang F, Jiang M et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 22, 593-599 (2008).
132. Baron F, Lechanteur C, Willems E et al. Cotransplantation of mesenchymal stem cells might prevent death from graft-versus-host disease (GVHD) without abrogating graft-versus-Tumor effects after HLA-mismatched allogeneic transplantation following nonmyeloablative conditioning. Biol. Blood Marrow Transplant. 16(6), 838-847 (2010).
133. Patel SA, Rameshwar P. Stem cell transplantation for hematological malignancies: prospects for personalized medicine and co-Therapy with mesenchymal stem cells. Curr. Pharmacogenomics Person. Med. 9(3), 229-239 (2011).
134. Tolar J, Le Blanc K, Blazar BR. MSCs for graft-versus-host disease. In: Mesenchymal Stromal Cells. Hematti P, Keating A (Eds). Springer, New York, NY, USA, 455-465 (2013).
135. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist 6(1), 34-55 (2001).
136. Ye Z, Wang Y, Xie HY, Zheng SS. Immunosuppressive effects of rat mesenchymal stem cells: involvement of CD4+CD25+ regulatory T-cells. Hepatobiliary Pancreat. Dis. Int. 7(6), 608-614 (2008).
137. Sudres M, Norol F, Trenado A et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J. Immunol. 176(12), 7761-7767 (2006).
138. Pollack A. A stem-cell-based drug gets approval in Canada. The New York Times, 17 May (2012).
139. Syed BA, Evans JB. Stem cell therapy market. Nat. Rev. Drug Discov. 12(3), 185-186 (2013).
140. ClinicalTrial Database: NCT00366145. https://clinicaltrials.gov/ct2/show/NCT00366145
141. Newell LF, Deans RJ, Maziarz RT. Adult adherent stromal cells in the management of graft-versus-host disease. Expert Opin. Biol. Ther. 14(2), 231-246 (2014).
142. Liu S, Ginestier C, Ou SJ et al. Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res. 71(2), 614-624 (2011).
143. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS ONE 5(4), e10088 (2010).
144. Waterman RS, Henkle SL, Betancourt AM. Mesenchymal stem cell 1 (MSC1)-based therapy attenuates tumor growth whereas MSC2-Treatment promotes tumor growth and metastasis. PLoS ONE 7(9), e45590 (2012).
145. Tolar J, Villeneuve P, Keating A. Mesenchymal stromal cells for graft-versus-host disease. Hum. Gene Ther. 22(3), 257-262 (2011).
146. Mantovani A. MSCs, macrophages, and cancer: a dangerous menage-A-Trois. Cell Stem Cell 11(6), 730-732 (2012).
147. Minoo B, Barrett AJ. Safety issues in MSC therapy. In: Mesenchymal Stromal Cells. Hematti P, Keating A (Eds). Springer, New York, NY, USA, 377-387 (2013).
148. Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd. Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29(1), 11-19 (2011).
149. Woods NB, Parker AS, Moraghebi R et al. Brief report: efficient generation of hematopoietic precursors and progenitors from human pluripotent stem cell lines. Stem Cells 29(7), 1158-1164 (2011).
150. Li C, George DR, Helton NM, Klco JM, Mudd JL, Ley TJ. Functional early hematopoietic progenitor cells derived from mouse embryonic stem cells and induced pluripotent stem cells. Blood 122, 2421 (2013).
151. Tabar V, Studer L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat. Rev. Genet. 15(2), 82-92 (2014).
152. Nakajima-Takagi Y, Osawa M, Iwama A. Manipulation of hematopoietic stem cells for regenerative medicine. Anat. Rec. (Hoboken) 297(1), 111-120 (2014).
153. Catapult https://ct.catapult.org.uk/multi-party-bloodpharmaconsortium-To-develop-synthetic-blood
154. WellcomeTrust www.wellcome.ac.uk/Funding/Innovations/Fundedprojects/ regenerative-medicine/index.htm.
155. Burrell BE, Nakayama Y, Xu J, Brinkman CC, Bromberg JS. Regulatory T-cell induction, migration, and function in transplantation. J. Immunol. 189(10), 4705-4711 (2012).
156. Schneidawind D, Pierini A, Negrin RS. Regulatory T-cells and natural killer T-cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122(18), 3116-3121 (2013).
157. Tang Q, Bluestone JA. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb. Perspect. Biol. 5(11), doi: 10.1101/cshperspect.a015552 (2013).
158. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T-cells. Immunity 38(3), 414-423 (2013).
159. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99(10), 3493-3499 (2002).
160. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-Type CD4(+)CD25(+) regulatory T-cells suppress lethal acute graft-versus-host disease after allogeneic blood marrow transplantation. J. Exp. Med. 196(3), 389-399 (2002).
161. Edinger M, Hoffmann P, Ermann J et al. CD4+CD25+ regulatory T-cells preserve graft-versus-Tumor activity while inhibiting graft-versus-host disease after blood marrow transplantation. Nat. Med. 9(9), 1144-1150 (2003).
162. Cao T, Soto A, Zhou W et al. Ex vivo expanded human CD4+CD25+Foxp3+ regulatory T-cells prevent lethal xenogenic graft versus host disease (GVHD). Cell. Immunol. 258(1), 65-71 (2009).
163. Mutis T, van Rijn RS, Simonetti ER et al. Human regulatory T-cells control xenogeneic graft-versus-host disease induced by autologous T-cells in RAG2-/-gammac-/-immunodeficient mice. Clin. Cancer Res. 12(18), 5520-5525 (2006).
164. Koenecke C, Czeloth N, Bubke A et al. Alloantigen-specific de novo-induced Foxp3+ Treg revert in vivo and do not protect from experimental GVHD. Eur J. Immunol. 39(11), 3091-3096 (2009).
165. Rieger K, Loddenkemper C, Maul J et al. Mucosal FOXP3+ regulatory T-cells are numerically deficient in acute and chronic GvHD. Blood 107(4), 1717-1723 (2006).
166. Zorn E, Kim HT, Lee SJ et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T-cells in patients with chronic graft-versus-host disease. Blood 106(8), 2903-2911 (2005).
167. Rezvani K, Mielke S, Ahmadzadeh M et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108(4), 1291-1297 (2006).
168. Miura Y, Thoburn CJ, Bright EC et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 104(7), 2187-2193 (2004).
169. Matsuoka K, Kim HT, Mcdonough S et al. Altered regulatory T-cell homeostasis in patients with CD4+ lymphopenia following allogeneic hematopoietic stem cell transplantation. J. Clin. Invest. 120(5), 1479-1493 (2010).
170. Brunstein CG, Miller JS, Cao Q et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3), 1061-1070 (2011).
171. Di Ianni M, Falzetti F, Carotti A et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117(14), 3921-3928 (2011).
172. Siegmund K, Feuerer M, Siewert C et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood 106(9), 3097-3104 (2005).
173. Maganto-Garcia E, Bu DX, Tarrio ML et al. Foxp3+-inducible regulatory T-cells suppress endothelial activation and leukocyte recruitment. J. Immunol. 187(7), 3521-3529 (2011).
174. Zarbock A, Ley K, Mcever RP, Hidalgo A. Leukocyte ligands for endothelial selectins: specialized glycoconjugates that mediate rolling and signaling under flow. Blood 118(26), 6743-6751 (2011).
175. Angiari S, Rossi B, Piccio L et al. Regulatory T-cells suppress the late phase of the immune response in lymph nodes through P-selectin glycoprotein ligand-1. J. Immunol. 191(11), 5489-5500 (2013).
176. Bollyky PL, Falk BA, Long SA et al. CD44 costimulation promotes FoxP3+ regulatory T-cell persistence and function via production of IL-2, IL-10, and TGF-beta. J. Immunol. 183(4), 2232-2241 (2009).
177. Bodduluru LN, Kasala ER, Madhana RM, Sriram CS. Natural killer cells: the journey from puzzles in biology to treatment of cancer. Cancer Lett. 357(2), 454-467 (2015).
178. Robertson MJ, Ritz J. Biology and clinical relevance of human natural killer cells. Blood 76(12), 2421-2438 (1990).
179. Murphy WJ, Reynolds CW, Tiberghien P, Longo DL. Natural killer cells and blood marrow transplantation. J. Natl Cancer Inst. 85(18), 1475-1482 (1993).
180. Asai O, Longo DL, Tian ZG et al. Suppression of graftversus-host disease and amplification of graft-versus-Tumor effects by activated natural killer cells after allogeneic blood marrow transplantation. J. Clin. Invest. 101(9), 1835-1842 (1998).
181. Klingemann HG. Cellular therapy of cancer with natural killer cells-where do we stand? Cytotherapy 15, 1185-1194 (2013).
182. Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NKcell proliferation. Blood 107(4), 1484-1490 (2006).
183. Lundqvist A, Mccoy JP, Samsel L, Childs R. Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donors. Blood 109(8), 3603-3606 (2007).
184. Ruggeri L, Capanni M, Urbani E et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562), 2097-2100 (2002).
185. Ljunggren HG, Malmberg KJ. Prospects for the use of NK cells in immunotherapy of human cancer. Nat. Rev. Immunol. 7(5), 329-339 (2007).
186. Leung W, Iyengar R, Turner V et al. Determinants of antileukemia effects of allogeneic NK cells. J. Immunol. 172(1), 644-650 (2004).
187. Murphy WJ, Longo DL. The potential role of NK cells in the separation of graft-versus-Tumor effects from graft-versus-host disease after allogeneic blood marrow transplantation. Immunol. Rev. 157, 167-176 (1997).
188. Tonn T, Schwabe D, Klingemann HG et al. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 15, 1563-1570 (2013).
189. Lazarus H, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Blood Marrow Transplant. 16(4), 557-564 (1995).
190. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat. Rev. Immunol. 8, 726-736 (2008).
191. Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 284(5411), 143-147 (1999).
192. Caplan AI. The MSC: an injury drugstore. Cell Stem Cell 9, 11-15 (2011).
193. Caplan AI. MSCs as therapeutics. In: Mesenchymal Stromal Cells. Hematti P, Keating A (Eds). Springer, New York, NY, USA, 79-90 (2013).
194. Dimarino AM, Caplan AI, Bonfield TL. Mesenchymal stem cells in tissue repair. Front. Immunol. 4, 201 (2013).
195. Keating A. Mesenchymal stromal cells: new directions. Cell Stem Cell 10(6), 709-716 (2012).
196. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat. Rev. Immunol. 12(5), 383-396 (2012).
197. Shi Y, Su J, Roberts AI, Rabson AB, Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 33, 136-143 (2012).
198. Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124(4), 823-835 (2006).
199. Prockop DJ. Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. Stem Cells 31(10), 2042-2046 (2013).
200. Deans RJ, Moseley AB. Mesenchymal stem cells: biology and potential clinical uses. Exp. Hematol. 28(8), 875-884 (2000).
201. Kaipe H, Erkers T, Sadeghi B, Ringden O. Stromal cells-Are they really useful for GVHD? Blood Marrow Transplant. 49(6), 737-743 (2014).
202. Herrmann RP, Sturm MJ. Adult human mesenchymal stromal cells and the treatment of graft versus host disease. Stem Cells Cloning 7, 45-52 (2014).
203. Kebriaei P, Robinson S. Treatment of graft-versus-host-disease with mesenchymal stromal cells. Cytotherapy 13(3), 262-268 (2011).
204. Gratwohl A, Niederwieser D. History of hematopoietic stem cell transplantation: evolution and perspectives. Curr. Probl. Dermatol. 43, 81-90 (2012).
205. Le Blanc K, Rasmusson I, Sundberg B et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363(9419), 1439-1441 (2004).
206. Le Blanc K, Frassoni F, Ball L et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versushost disease: a phase II study. Lancet 371(9624), 1579-1586 (2008).
207. Ringden O, Erkers T, Nava S et al. Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells 31(3), 592-601 (2013).
208. von Bahr L, Sundberg B, Lonnies L et al. Long-Term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol. Blood Marrow Transplant. 18(4), 557-564 (2012).
209. Remberger M, Ringden O. Treatment of severe acute graft-versus-host disease with mesenchymal stromal cells: a comparison with non-MSC treated patients. Int. J. Hematol. 96(6), 822-824 (2012).
210. Forslöw U, Blennow O, Leblanc K et al. Treatment with mesenchymal stromal cells is a risk factor for pneumoniarelated death after allogeneic hematopoietic stem cell transplantation. Eur. J. Haematol. 89(3), 220-227 (2012).
211. Uhlin M, Wikell H, Sundin M et al. Risk factors for Epstein Barr virus related post-Transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica 99(2), 346-352 (2013).
212. Moermans C, Lechanteur C, Baudoux E et al. Impact of cotransplantation of mesenchymal stem cells on lung function after unrelated allogeneic hematopoietic stem cell transplantation following non-myeloablative conditioning. Transplantation 98(3), 348-353 (2014).
213. Uhlin M, Sairafi D, Berglund S et al. Mesenchymal stem cells inhibit thymic reconstitution after allogeneic cord blood transplantation. Stem Cells Dev. 21(9), 1409-1417 (2012).
214. Resnick IB, Barkats C, Shapira MY et al. Treatment of severe steroid resistant acute GVHD with mesenchymal stromal cells (MSC). Am. J. Blood Res. 3(3), 225-238 (2013).
215. Ringden O, Le Blanc K. Mesenchymal stem cells for treatment of acute and chronic graft-versus-host disease, tissue toxicity and hemorrhages. Best Pract. Res. Clin. Haematol. 24(1), 65-72 (2011).
216. Wernicke CM, Grunewald TG, Juenger H et al. Mesenchymal stromal cells for treatment of steroid-refractory GvHD: a review of the literature and two pediatric cases. Int. Arch. Med. 4(1), 27 (2011).
217. Perez-Simon JA, Lopez-Villar O, Andreu EJ et al. Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graftversus-host disease: results of a Phase I/II clinical trial. Haematologica 96(7), 1072-1076 (2011).
218. Weng JY, Du X, Geng SX et al. Mesenchymal stem cell as salvage treatment for refractory chronic GvHD. Blood Marrow Transplant. 45, 1732-1740 (2010).
219. Ringden O, Keating A. Mesenchymal stromal cells as treatment for chronic GvHD. Blood Marrow Transplant. 46, 163-164 (2011).
220. Baker M. Stem-cell drug fails crucial trials. Nat. Rep. Stem Cellsdoi:10.1038/news.2009.894 (2009).
221. Prochymal Expanded Access Treatment for Pediatric Patients Who Have Failed Steroids for Acute GvHD. United States National Institute of Health NCT00759018. https:// clinicaltrials.gov/ct2/show/NCT00759018
222. Kurtzberg J, Prockop S, Teira P, et al. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients . J. Am. Soc. Blood Marrow Transplant. 20(2), 229-235 (2014).
223. Li MD, Atkins H, Bubela T. The global landscape of stem cell clinical trials. Regen. Med. 9(1), 27-39 (2014).
224. Zheng GP, Ge MH, Shu Q, Rojas M, Xu J. Mesenchymal stem cells in the treatment of pediatric diseases. World J. Pediatr. 9(3), 197-211 (2013).
225. Goodrich AD, Hematti P. Mesenchymal stem cell therapies: the quest for fine-Tuning. Exp. Dermatol. 23(9), 632-633 (2014).
226. Graft Versus Host Disease (GVHD) Therapeutics-Pipeline Assessment and Market Forecasts to 2018. (GDHC286PRT). www.clinicaltrials.gov 227 Clinical Trials http://clinicaltrials.gov/
227. Deans R. Regulation, manufacturing and building industry consensus. Regen. Med. 7(6 Suppl.), 78-81 (2012).
228. Report from the Commission to the European Parliament and the Council in accordance with Article 25 of Regulation (EC) No 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. 28 March. http://ec.europa.eu/health/files/advtherapies/2014-Atmp/ atmp-en.pdf
229. Safety Study of MultiStem in Patients With Acute Leukemia, Chronic Myeloid Leukemia, or Myelodysplasia. US National Institute of Health NCT00677859. https://clinicaltrials.gov/ct2/show/NCT00677859
230. A single-Arm Safety Study of Transplantation Using Umbilical Cord Blood and Human Placental-derived Stem Cells From Partially Matched Related Donors in Persons with Certain Malignant Blood Diseases and Non-malignant Disorders (HPDSC). US National Institute of Health NCT00596999. www.clinicaltrials.gov/ct2/show/NCT00596999
231. Athersys Announces Meeting With FDA to Discuss Advancing Clinical Development of MultiStem for the Prevention of GvHD. Press release 27 April http://ir.athersys.com/releasedetail.cfm?ReleaseID=668015
232. Maziarz RT, Devos T, Bachier C et al. Prophylaxis of acute GVHD using multistem stromal cell therapy: preliminary results after administration of single or multiple doses in a Phase 1 trial. Biol. Blood Marrow Transplant. 18(2), S264-S265 (2012).
233. Vaes B, Van't Hof W, Deans R, Pinxteren J. Application of MultiStem((R)) Allogeneic Cells for Immunomodulatory Therapy: Clinical Progress and Pre-Clinical Challenges in Prophylaxis for Graft Versus Host Disease. Front. Immunol. 3, 345 (2012).
234. Schulze U, Ringel M. What matters most in commercial success: first-in-class or best-in-class? Nat. Rev. Drug Discov. 12(6), 419-420 (2013).
235. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp. Hematol. 31(10), 890-896 (2003).
236. Potian JA, Aviv H, Ponzio NM, Harrison JS, Rameshwar P. Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J. Immunol. 171(7), 3426-3434 (2003).
237. Dazzi F, Van Laar JM, Cope A, Tyndall A. Cell therapy for autoimmune diseases. Arthritis Res. Ther. 9(2), 206 (2007).
238. Levine JE, Logan BR, Wu J et al. Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 119(16), 3854-3860 (2012).
239. Andrew C, Harris AC, Levine JE, Ferrara JLM. Have we made progress in the treatment of GvHD? Best Pract. Res. Clin. Haematol. 25(4), 473-478 (2012).
240. Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. Blood 121(4), 585-594 (2013).
241. MSCs Combined with CD25 Monoclonal Antibody and Calcineurin Inhibitors for Treatment of Steroid-Resistant aGVHD. United States National Institute of Health NCT02241018 https://clinicaltrials.gov
242. Esneault E, Pacary E, Eddi D et al. Combined therapeutic strategy using erythropoietin and mesenchymal stem cells potentiates neurogenesis after transient focal cerebral ischemia in rats. J. Cereb. Blood Flow Metab. 28(9), 1552-1563 (2008).
243. Efficacy and Safety of Prochymal Infusion in Combination With Corticosteroids for the Treatment of Newly Diagnosed Acute GVHD. United States National Institute of Health NCT00562497. https://clinicaltrials.gov/ct2/show/ NCT00562497
244. Umbilical Cord Mesenchymal Stem Cells and Liraglutide in Diabetes Mellitus. United States National Institute of Health NCT01954147. https://clinicaltrials.gov
245. Cook MM, Futrega K, Osiecki M et al. Micromarrows-Three-dimensional coculture of hematopoietic stem cells and mesenchymal stromal cells. Tissue Eng. Part C Methods 18(5), 319-328 (2012).
246. Chinnadurai R, Galipeau J. Defining mesenchymal stromal cells responsiveness to IFN? as a surrogate measure of suppressive potency. Inflamm. Regen. 34(4), 168-175 (2014).
247. Abdi R, Fiorina P, Adra CN, Atkinson M, Sayegh MH. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for Type 1 diabetes. Diabetes 57(7), 1759-1767 (2008).
248. Ezquer F, Ezquer M, Contador D, Ricca M, Simon V, Conget P. The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells 30(8), 1664-1674 (2012).
249. Adorable-Wagan P, Bernal S, Lavilles D, De Vera M. The safety of bone-marrow derived mesenchymal stem cells in patients with Type 2 diabetes mellitus. Cytotherapy 16(4), S82 (2014).
250. Donath MY. Targeting inflammation in the treatment of Type 2 diabetes: time to start. Nat. Rev. Drug Discov. 13(6), 465-476 (2014).
251. ClinicalTrials Database: NCT01576328. https://clinicaltrials.gov/ct2/show/NCT01576328
252. ClinicalTrials Database: NCT00136903. https://clinicaltrials.gov/ct2/show/NCT00136903
253. ClinicalTrials Database: NCT00284986. https://clinicaltrials.gov/ct2/show/NCT00284986
254. ClinicalTrials Database: NCT01318330. https://clinicaltrials.gov/ct2/show/NCT01318330
255. ClinicalTrials Database: NCT00823316. https://clinicaltrials.gov/ct2/show/NCT00823316
256. ClinicalTrials Database: NCT01549665. https://clinicaltrials.gov/ct2/results?term=NCT01549665
257. ClinicalTrials Database: NCT01222039. https://clinicaltrials.gov/ct2/show/NCT01222039
258. ClinicalTrials Database: NCT01956903. https://clinicaltrials.gov/ct2/show/NCT01956903
259. ClinicalTrials Database: NCT00447460. https://clinicaltrials.gov/ct2/show/NCT00447460
260. ClinicalTrials Database: NCT01764100. https://clinicaltrials.gov/ct2/show/NCT01764100
261. ClinicalTrials Database: NCT02055625. https://clinicaltrials.gov/ct2/show/NCT02055625
262. ClinicalTrials Database: NCT00827398. https://clinicaltrials.gov/ct2/show/NCT00827398
263. ClinicalTrials Database: NCT00524784. https://clinicaltrials.gov/ct2/show/NCT00524784
264. ClinicalTrials Database: NCT00749164. https://clinicaltrials.gov/ct2/show/NCT00749164
265. ClinicalTrials Database: NCT01633229. https://clinicaltrials.gov/ct2/show/NCT01633229
266. ClinicalTrials Database: NCT00361049. https://clinicaltrials.gov/ct2/show/NCT00361049
267. ClinicalTrials Database: NCT01795573. https://clinicaltrials.gov/ct2/show/NCT01795573
268. ClinicalTrials Database: NCT00081055. https://clinicaltrials.gov/ct2/show/NCT00081055
269. ClinicalTrials Database: NCT01589549. https://clinicaltrials.gov/ct2/show/NCT01589549
270. ClinicalTrials Database: NCT01941394. https://clinicaltrials.gov/ct2/show/NCT01941394
271. ClinicalTrials Database: NCT01765634. https://clinicaltrials.gov/ct2/show/NCT01765634
272. ClinicalTrials Database: NCT01765660. https://clinicaltrials.gov/ct2/show/NCT01765660
273. ClinicalTrials Database: NCT02240992. https://clinicaltrials.gov/ct2/show/NCT02240992
274. ClinicalTrials Database: NCT01754454. https://clinicaltrials.gov/ct2/show/NCT01754454
275. ClinicalTrials Database: NCT00972660. https://clinicaltrials.gov/ct2/show/NCT00972660
276. ClinicalTrials Database: NCT01526850. https://clinicaltrials.gov/ct2/show/NCT01526850
277. ClinicalTrials Database: NCT00314483. https://clinicaltrials.gov/ct2/show/NCT00314483
278. ClinicalTrials Database: NCT00504803 https://clinicaltrials.gov/ct2/show/NCT00504803
279. ClinicalTrials Database: NCT00603330 https://clinicaltrials.gov/ct2/show/NCT00603330