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Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?

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Biobanking and Cryopreservation of Stem Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 951))

Abstract

Mesenchymal stromal cells (MSCs) harbor great therapeutic potential for numerous diseases. From early clinical trials, success and failure analysis, bench-to-bedside and back-to-bench approaches, there has been a great gain in knowledge, still leaving a number of questions to be answered regarding optimal manufacturing and quality of MSCs for clinical application. For treatment of many acute indications, cryobanking may remain a prerequisite, but great uncertainty exists considering the therapeutic value of freshly thawed (thawed) and continuously cultured (fresh) MSCs. The field has seen an explosion of new literature lately, outlining the relevance of the topic. MSCs appear to have compromised immunomodulatory activity directly after thawing for clinical application. This may provide a possible explanation for failure of early clinical trials. It is not clear if and how quickly MSCs recover their full therapeutic activity, and if the “cryo stun effect” is relevant for clinical success. Here, we will share our latest insights into the relevance of these observations for clinical practice that will be discussed in the context of the published literature. We argue that the differences of fresh and thawed MSCs are limited but significant. A key issue in evaluating potency differences is the time point of analysis after thawing. To date, prospective double-blinded randomized clinical studies to evaluate potency of both products are lacking, although recent progress was made with preclinical assessment. We suggest refocusing therapeutic MSC development on potency and safety assays with close resemblance of the clinical reality.

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Abbreviations

AT:

Adipose tissue

ATMP:

Advanced therapy medicinal product

BM:

Bone marrow

CD3:

Cluster of differentiation 3

CPA:

Cryoprotective agent

DMSO:

Dimethyl sulfoxide

FCS:

Fetal calf serum

GvHD:

Graft-versus-host disease

IBMIR:

Instant blood-mediated inflammatory reaction

IFNg:

Interferon gamma

IL1a:

Interleukin 1 alpha

ISCT:

International Society for Cellular Therapy

LN2:

Liquid nitrogen

MOA:

Mechanism of action

MSC:

Mesenchymal stromal cell

NK cell:

Natural killer cell

PBMC:

Peripheral blood mononuclear cell

RNA:

Ribonucleic acid

T1D:

Type 1 diabetes

TNFa:

Tumor necrosis factor alpha

UC:

Umbilical cord

References

  1. Baust JM, Corwin WL, VanBuskirk R, Baust JG (2015) Biobanking: the future of cell preservation strategies. Adv Exp Med Biol 864:37–53

    Article  PubMed  Google Scholar 

  2. Stacey GN, Day JG (2014) Putting cells to sleep for future science. Nat Biotechnol 32:320–322

    Article  CAS  PubMed  Google Scholar 

  3. Galipeau J (2013) Concerns arising from MSC retrieval from cryostorage and effect on immune suppressive function and pharmaceutical usage in clinical trials. ISBT Sci Ser 8:100–101

    Article  Google Scholar 

  4. Galipeau J (2013) The mesenchymal stromal cells dilemma-does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15:2–8

    Article  PubMed  Google Scholar 

  5. Galipeau J, Krampera M, Barrett J, Dazzi F, Deans RJ, DeBruijn J, Dominici M, Fibbe WE, Gee AP, Gimble JM, Hematti P, Koh MB, LeBlanc K, Martin I, McNiece IK, Mendicino M, Oh S, Ortiz L, Phinney DG, Planat V, Shi Y, Stroncek DF, Viswanathan S, Weiss DJ, Sensebe L (2016) International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 18:151–159

    Article  CAS  PubMed  Google Scholar 

  6. Moll G, Le Blanc K (2015) Engineering more efficient multipotent mesenchymal stromal (stem) cells for systemic delivery as cellular therapy. ISBT Sci Ser 10:357–365

    Article  Google Scholar 

  7. Luk F, de Witte SF, Bramer WM, Baan CC, Hoogduijn MJ (2015) Efficacy of immunotherapy with mesenchymal stem cells in man: a systematic review. Expert Rev Clin Immunol 11:617–636

    Article  CAS  PubMed  Google Scholar 

  8. Schepers K, Fibbe WE (2016) Unraveling mechanisms of mesenchymal stromal cell-mediated immunomodulation through patient monitoring and product characterization. Ann N Y Acad Sci 1370:15–23

    Google Scholar 

  9. Marquez-Curtis LA, Janowska-Wieczorek A, McGann LE, Elliott JA (2015) Mesenchymal stromal cells derived from various tissues: biological, clinical and cryopreservation aspects. Cryobiology 71:181–197

    Article  CAS  PubMed  Google Scholar 

  10. Yong KW, Wan Safwani WK, Xu F, Wan Abas WA, Choi JR, Pingguan-Murphy B (2015) Cryopreservation of human mesenchymal stem cells for clinical applications: current methods and challenges. Biopreserv Biobank 13:231–239

    Article  PubMed  Google Scholar 

  11. Kaipe H, Erkers T, Sadeghi B, Ringden O (2014) Stromal cells-are they really useful for GVHD? Bone Marrow Transplant 49:737–743

    Article  CAS  PubMed  Google Scholar 

  12. Martin PJ, Inamoto Y, Flowers ME, Carpenter PA (2012) Secondary treatment of acute graft-versus-host disease: a critical review. Biol Blood Marrow Transplant 18:982–988

    Article  PubMed  PubMed Central  Google Scholar 

  13. Moll G, Rasmusson-Duprez I, von Bahr L, Connolly-Andersen AM, Elgue G, Funke L, Hamad OA, Lonnies H, Magnusson PU, Sanchez J, Teramura Y, Nilsson-Ekdahl K, Ringden O, Korsgren O, Nilsson B, Le Blanc K (2012) Are therapeutic human mesenchymal stromal cells compatible with human blood? Stem Cells 30:1565–1574

    Article  CAS  PubMed  Google Scholar 

  14. Moll G, Alm JJ, Davies LC, von Bahr L, Heldring N, Stenbeck-Funke L, Hamad OA, Hinsch R, Ignatowicz L, Locke M, Lonnies H, Lambris JD, Teramura Y, Nilsson-Ekdahl K, Nilsson B, Le Blanc K (2014) Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells 32:2430–2442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Moll G, Hult A, von Bahr L, Alm JJ, Heldring N, Hamad OA, Stenbeck-Funke L, Larsson S, Teramura Y, Roelofs H, Nilsson B, Fibbe WE, Olsson ML, Le Blanc K (2014) Do ABO blood group antigens hamper the therapeutic efficacy of mesenchymal stromal cells? PLoS ONE 9, e85040

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Moll G, Ignatowicz L, Catar R, Luecht C, Sadeghi B, Hamad O, Jungebluth P, Dragun D, Schmidtchen A, Ringden O (2015) Different procoagulant activity of therapeutic mesenchymal stromal cells derived from bone marrow and placental decidua. Stem Cells Dev 24:2269–2279

    Article  CAS  PubMed  Google Scholar 

  17. Gleeson BM, Martin K, Ali MT, Kumar AH, Pillai MG, Kumar SP, O’Sullivan JF, Whelan D, Stocca A, Khider W, Barry FP, O’Brien T, Caplice NM (2015) Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by anti-thrombin therapy. Stem Cells 33:2726–2737

    Article  CAS  PubMed  Google Scholar 

  18. Hoogduijn MJ, de Witte SF, Luk F, van den Hout-van Vroonhoven MC, Ignatowicz L, Catar R, Strini T, Korevaar SS, van IJcken WF, Betjes MG, Franquesa M, Moll G, Baan CC (2016) Effects of freeze-thawing and intravenous infusion on mesenchymal stromal cell gene expression. Stem Cells Dev 25:586–597

    Article  CAS  PubMed  Google Scholar 

  19. Hoogduijn MJ, Roemeling-van Rhijn M, Engela AU, Korevaar SS, Mensah FK, Franquesa M, de Bruin RW, Betjes MG, Weimar W, Baan CC (2013) Mesenchymal stem cells induce an inflammatory response after intravenous infusion. Stem Cells Dev 22:2825–2835

    Article  CAS  PubMed  Google Scholar 

  20. Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: an update. Cell Transplant 25:829–848

    Article  PubMed  Google Scholar 

  21. Kuci Z, Bonig H, Kreyenberg H, Bunos M, Jauch A, Janssen JW, Skific M, Michel K, Eising B, Lucchini G, Bakhtiar S, Greil J, Lang P, Basu O, von Luettichau I, Schultz A, Sykora KW, Jarisch A, Soerensen J, Salzmann-Manrique E, Seifried E, Klingebiel T, Bader P, Kuci S (2016) Mesenchymal stromal cells generated from pooled mononuclear cells of multiple bone marrow donors as a rescue therapy for children with severe steroid-refractory graft versus host disease: a multicenter survey. Haematologica 101(8):985–994

    Article  PubMed  PubMed Central  Google Scholar 

  22. Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736

    Article  CAS  PubMed  Google Scholar 

  23. Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12:383–396

    Article  PubMed  CAS  Google Scholar 

  24. Doorn J, Moll G, Le Blanc K, van Blitterswijk C, de Boer J (2012) Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Eng B Rev 18:101–115

    Article  CAS  Google Scholar 

  25. Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR (2014) MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14:141–145

    Article  CAS  PubMed  Google Scholar 

  26. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301

    Article  CAS  PubMed  Google Scholar 

  27. Stubbendorff M, Deuse T, Hua X, Phan TT, Bieback K, Atkinson K, Eiermann TH, Velden J, Schroder C, Reichenspurner H, Robbins RC, Volk HD, Schrepfer S (2013) Immunological properties of extraembryonic human mesenchymal stromal cells derived from gestational tissue. Stem Cells Dev 22:2619–2629

    Article  CAS  PubMed  Google Scholar 

  28. Parolini O, Alviano F, Bagnara GP, Bilic G, Buhring HJ, Evangelista M, Hennerbichler S, Liu B, Magatti M, Mao N, Miki T, Marongiu F, Nakajima H, Nikaido T, Portmann-Lanz CB, Sankar V, Soncini M, Stadler G, Surbek D, Takahashi TA, Redl H, Sakuragawa N, Wolbank S, Zeisberger S, Zisch A, Strom SC (2008) Concise review: isolation and characterization of cells from human term placenta: outcome of the first international Workshop on Placenta Derived Stem Cells. Stem Cells 26:300–311

    Article  PubMed  Google Scholar 

  29. Ringden O, Erkers T, Nava S, Uzunel M, Iwarsson E, Conrad R, Westgren M, Mattsson J, Kaipe H (2013) Fetal membrane cells for treatment of steroid-refractory acute graft-versus-host disease. Stem Cells 31:592–601

    Article  CAS  PubMed  Google Scholar 

  30. Ringdén O (2014) Placenta-derived decidual stromal cells – a novel therapy for graft-versus-host disease, haemorrhages and toxicity after allogeneic haematopoietic stem cell transplantation

    Google Scholar 

  31. Wang H, Liang X, Xu ZP, Crawford DH, Liu X, Roberts MS (2016) A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells. Sci Rep 6:22293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Leibacher J, Henschler R (2016) Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther 7:7

    Article  PubMed  PubMed Central  Google Scholar 

  33. Eggenhofer E, Benseler V, Kroemer A, Popp FC, Geissler EK, Schlitt HJ, Baan CC, Dahlke MH, Hoogduijn MJ (2012) Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 3:297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringden O (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586

    Article  PubMed  CAS  Google Scholar 

  35. von Bahr L, Sundberg B, Lonnies L, Sander B, Karbach H, Hagglund H, Ljungman P, Gustafsson B, Karlsson H, Le Blanc K, Ringden O (2012) Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 18:557–564

    Article  Google Scholar 

  36. Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H, Marschall HU, Dlugosz A, Szakos A, Hassan Z, Omazic B, Aschan J, Barkholt L, Le Blanc K (2006) Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81:1390–1397

    Article  PubMed  Google Scholar 

  37. von Dalowski F, Kramer M, Wermke M, Wehner R, Rollig C, Alakel N, Stolzel F, Parmentier S, Sockel K, Krech M, Schmitz M, Platzbecker U, Schetelig J, Bornhauser M, von Bonin M (2016) Mesenchymal stromal cells for treatment of acute steroid-refractory graft versus host disease: clinical responses and long-term outcome. Stem Cells 34:357–366

    Article  CAS  Google Scholar 

  38. Perez-Simon JA, Lopez-Villar O, Andreu EJ, Rifon J, Muntion S, Diez Campelo M, Sanchez-Guijo FM, Martinez C, Valcarcel D, Canizo CD (2011) Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica 96:1072–1076

    Article  PubMed  PubMed Central  Google Scholar 

  39. Arima N, Nakamura F, Fukunaga A, Hirata H, Machida H, Kouno S, Ohgushi H (2010) Single intra-arterial injection of mesenchymal stromal cells for treatment of steroid-refractory acute graft-versus-host disease: a pilot study. Cytotherapy 12:265–268

    Article  PubMed  Google Scholar 

  40. Kinzebach S, Dietz L, Kluter H, Thierse HJ, Bieback K (2013) Functional and differential proteomic analyses to identify platelet derived factors affecting ex vivo expansion of mesenchymal stromal cells. BMC Cell Biol 14:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dreher L, Elvers-Hornung S, Brinkmann I, Huck V, Henschler R, Gloe T, Kluter H, Bieback K (2013) Cultivation in human serum reduces adipose tissue-derived mesenchymal stromal cell adhesion to laminin and endothelium and reduces capillary entrapment. Stem Cells Dev 22:791–803

    Article  CAS  PubMed  Google Scholar 

  42. Bieback K, Hecker A, Schlechter T, Hofmann I, Brousos N, Redmer T, Besser D, Kluter H, Muller AM, Becker M (2012) Replicative aging and differentiation potential of human adipose tissue-derived mesenchymal stromal cells expanded in pooled human or fetal bovine serum. Cytotherapy 14:570–583

    Article  CAS  PubMed  Google Scholar 

  43. Bieback K, Ha VA, Hecker A, Grassl M, Kinzebach S, Solz H, Sticht C, Kluter H, Bugert P (2010) Altered gene expression in human adipose stem cells cultured with fetal bovine serum compared to human supplements. Tissue Eng A 16:3467–3484

    Article  CAS  Google Scholar 

  44. Bieback K, Hecker A, Kocaomer A, Lannert H, Schallmoser K, Strunk D, Kluter H (2009) Human alternatives to fetal bovine serum for the expansion of mesenchymal stromal cells from bone marrow. Stem Cells 27:2331–2341

    Article  CAS  PubMed  Google Scholar 

  45. Kocaoemer A, Kern S, Kluter H, Bieback K (2007) Human AB serum and thrombin-activated platelet-rich plasma are suitable alternatives to fetal calf serum for the expansion of mesenchymal stem cells from adipose tissue. Stem Cells 25:1270–1278

    Article  CAS  PubMed  Google Scholar 

  46. Gross G, Häupl T (2013) Stem cell-dependent therapies, mesenchymal stem cells in chronic inflammatory disorders

    Google Scholar 

  47. Hashmi S, Ahmed M, Murad MH, Litzow MR, Adams RH, Ball LM, Prasad VK, Kebriaei P, Ringden O (2016) Survival after mesenchymal stromal cell therapy in steroid-refractory acute graft-versus-host disease: systematic review and meta-analysis. Lancet Haematol 3:e45–e52

    Article  PubMed  Google Scholar 

  48. Fang B, Song Y, Zhao RC, Han Q, Lin Q (2007) Using human adipose tissue-derived mesenchymal stem cells as salvage therapy for hepatic graft-versus-host disease resembling acute hepatitis. Transplant Proc 39:1710–1713

    Article  CAS  PubMed  Google Scholar 

  49. Wu KH, Chan CK, Tsai C, Chang YH, Sieber M, Chiu TH, Ho M, Peng CT, Wu HP, Huang JL (2011) Effective treatment of severe steroid-resistant acute graft-versus-host disease with umbilical cord-derived mesenchymal stem cells. Transplantation 91:1412–1416

    Article  PubMed  Google Scholar 

  50. Martin PJ, Uberti JP, Soiffer RJ, Klingemann H, Waller EK, Daly AS, Herrmann RP, Kebriaei P (2010) Prochymal improves response rates in patients with Steroid-Refractory Acute Graft Versus Host Disease (SR-GVHD) involving the liver and gut: results of a randomized, placebo-controlled, multicenter phase III trial in GVHD. Biol Blood Marrow Transplant 16:S169–S170

    Google Scholar 

  51. Kurtzberg J, Prockop S, Teira P, Bittencourt H, Lewis V, Chan KW, Horn B, Yu L, Talano JA, Nemecek E, Mills CR, Chaudhury S (2014) Allogeneic human mesenchymal stem cell therapy (remestemcel-L, prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 20:229–235

    Article  Google Scholar 

  52. Ball LM, Bernardo ME, Roelofs H, van Tol MJ, Contoli B, Zwaginga JJ, Avanzini MA, Conforti A, Bertaina A, Giorgiani G, der Zijde CM J-v, Zecca M, Le Blanc K, Frassoni F, Egeler RM, Fibbe WE, Lankester AC, Locatelli F (2013) Multiple infusions of mesenchymal stromal cells induce sustained remission in children with steroid-refractory, grade III–IV acute graft-versus-host disease. Br J Haematol 163:501–509

    Article  CAS  PubMed  Google Scholar 

  53. Ringden O, Leblanc K (2011) Pooled MSCs for treatment of severe hemorrhage. Bone Marrow Transplant 46:1158–1160

    Article  CAS  PubMed  Google Scholar 

  54. Jitschin R, Mougiakakos D, Von Bahr L, Volkl S, Moll G, Ringden O, Kiessling R, Linder S, Le Blanc K (2013) Alterations in the cellular immune compartment of patients treated with third-party mesenchymal stromal cells following allogeneic hematopoietic stem cell transplantation. Stem Cells 31:1715–1725

    Article  CAS  PubMed  Google Scholar 

  55. Krampera M (2011) Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia 25:1408–1414

    Article  CAS  PubMed  Google Scholar 

  56. Galipeau J, Krampera M (2015) The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria. Cytotherapy 17:125–127

    Article  PubMed  Google Scholar 

  57. Ren G, Zhang L, Zhao X, Xu G, Zhang Y, Roberts AI, Zhao RC, Shi Y (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2:141–150

    Article  CAS  PubMed  Google Scholar 

  58. Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, Akyuz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD, Duda GN (2013) Terminally differentiated CD8(+) T cells negatively affect bone regeneration in humans. Sci Transl Med 5:177ra136

    Article  CAS  Google Scholar 

  59. Ketterl N, Brachtl G, Schuh C, Bieback K, Schallmoser K, Reinisch A, Strunk D (2015) A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance. Stem Cell Res Ther 6:236

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Börger V, Bremer M, Görgens A, Giebel B (2016) Mesenchymal stem/stromal cell-derived extracellular vesicles as a new approach in stem cell therapy. ISBT Sci Ser 11:228–234

    Article  Google Scholar 

  61. Rani S, Ryan AE, Griffin MD, Ritter T (2015) Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther 23:812–823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, Montgomery EN, Mellema MS, Bardini RL, Contreras Z, Hoon M, Bauer G, Fink KD, Fury B, Hendrix KJ, Chedin F, El-Andaloussi S, Hwang B, Mulligan MS, Lehtio J, Nolta JA (2016) Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-KappaB signaling. Stem Cells 34:601–613

    Article  CAS  PubMed  Google Scholar 

  63. Koniusz S, Andrzejewska A, Muraca M, Srivastava AK, Janowski M, Lukomska B (2016) Extracellular vesicles in physiology, pathology and therapy of the immune and central nervous system, with focus on extracellular vesicles derived from mesenchymal stem cells as therapeutic tools. Front Cell Neurosci 10:109

    Article  PubMed  PubMed Central  Google Scholar 

  64. Merino-Gonzalez C, Zuniga FA, Escudero C, Ormazabal V, Reyes C, Nova-Lamperti E, Salomon C, Aguayo C (2016) Mesenchymal stem cell-derived extracellular vesicles promote angiogenesis: potencial clinical application. Front Physiol 7:24

    Article  PubMed  PubMed Central  Google Scholar 

  65. Phinney DG, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix CM, Stolz DB, Watkins SC, Di YP, Leikauf GD, Kolls J, Riches DW, Deiuliis G, Kaminski N, Boregowda SV, McKenna DH, Ortiz LA (2015) Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 6:8472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bernardo ME, Locatelli F, Fibbe WE (2009) Mesenchymal stromal cells. Ann N Y Acad Sci 1176:101–117

    Article  CAS  PubMed  Google Scholar 

  67. Singer NG, Caplan AI (2011) Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol 6:457–478

    Article  CAS  PubMed  Google Scholar 

  68. Bernardo ME, Fibbe WE (2013) Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell 13:392–402

    Article  CAS  PubMed  Google Scholar 

  69. Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y (2014) Immunobiology of mesenchymal stem cells. Cell Death Differ 21:216–225

    Article  CAS  PubMed  Google Scholar 

  70. Chhabra P, Brayman KL (2013) Stem cell therapy to cure type 1 diabetes: from hype to hope. Stem Cells Transl Med 2:328–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hematti P, Kim J, Stein AP, Kaufman D (2013) Potential role of mesenchymal stromal cells in pancreatic islet transplantation. Transplant Rev (Orlando) 27:21–29

    Article  Google Scholar 

  72. Carlsson PO, Schwarcz E, Korsgren O, Le Blanc K (2015) Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes 64:587–592

    Article  CAS  PubMed  Google Scholar 

  73. Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD, Prockop DJ (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 103:17438–17443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Urban VS, Kiss J, Kovacs J, Gocza E, Vas V, Monostori E, Uher F (2008) Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26:244–253

    Article  CAS  PubMed  Google Scholar 

  75. Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yanez AJ, Conget PA (2008) Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 14:631–640

    Article  CAS  PubMed  Google Scholar 

  76. Ho JH, Tseng TC, Ma WH, Ong WK, Chen YF, Chen MH, Lin MW, Hong CY, Lee OK (2012) Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and beta-cell differentiation in streptozocin-induced diabetic mice. Cell Transplant 21:997–1009

    Article  PubMed  Google Scholar 

  77. Lavoie JR, Creskey MC, Muradia G, Bell GI, Sherman SE, Gao J, Stewart DJ, Cyr TD, Hess DA, Rosu-Myles M (2016) EMILIN-1 and ILK are novel markers of islet regenerative function in human multipotent mesenchymal stromal cells. Stem Cells 34:2249–2255

    Article  CAS  PubMed  Google Scholar 

  78. Horwitz EM (2013) Advancing regenerative medicine the translational way. Sci Transl Med 5:177fs179

    Article  CAS  Google Scholar 

  79. Le Blanc K, Rasmusson I, Sundberg B, Gotherstrom C, Hassan M, Uzunel M, Ringden O (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441

    Article  PubMed  Google Scholar 

  80. Griffin MD, Elliman SJ, Cahill E, English K, Ceredig R, Ritter T (2013) Concise review: adult mesenchymal stromal cell therapy for inflammatory diseases: how well are we joining the dots? Stem Cells 31:2033–2041

    Article  CAS  PubMed  Google Scholar 

  81. von Bahr L, Batsis I, Moll G, Hagg M, Szakos A, Sundberg B, Uzunel M, Ringden O, Le Blanc K (2012) Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30:1575–1578

    Article  CAS  Google Scholar 

  82. Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (2002) 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 99:8932–8937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Wagner B, Henschler R (2013) Fate of intravenously injected mesenchymal stem cells and significance for clinical application. Adv Biochem Eng Biotechnol 130:19–37

    PubMed  Google Scholar 

  84. Erkers T, Kaipe H, Nava S, Mollden P, Gustafsson B, Axelsson R, Ringden O (2015) Treatment of severe chronic graft-versus-host disease with decidual stromal cells and tracing with (111)indium radiolabeling. Stem Cells Dev 24:253–263

    Article  CAS  PubMed  Google Scholar 

  85. Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216

    Article  CAS  PubMed  Google Scholar 

  86. Braun J, Kurtz A, Barutcu N, Bodo J, Thiel A, Dong J (2013) Concerted regulation of CD34 and CD105 accompanies mesenchymal stromal cell derivation from human adventitial stromal cell. Stem Cells Dev 22:815–827

    Article  CAS  PubMed  Google Scholar 

  87. Hoogduijn MJ, van den Beukel JC, Wiersma LC, Ijzer J (2013) Morphology and size of stem cells from mouse and whale: observational study. BMJ 347:f6833

    Article  PubMed  PubMed Central  Google Scholar 

  88. Ankrum JA, Ong JF, Karp JM (2014) Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 32:252–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Fischer UM, Harting MT, Jimenez F, Monzon-Posadas WO, Xue H, Savitz SI, Laine GA, Cox CS Jr (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692

    Article  CAS  PubMed  Google Scholar 

  90. Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169:12–20

    Article  CAS  PubMed  Google Scholar 

  91. Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP (2007) Stem cell transplantation: the lung barrier. Transplant Proc 39:573–576

    Article  CAS  PubMed  Google Scholar 

  92. Yukawa H, Watanabe M, Kaji N, Okamoto Y, Tokeshi M, Miyamoto Y, Noguchi H, Baba Y, Hayashi S (2012) Monitoring transplanted adipose tissue-derived stem cells combined with heparin in the liver by fluorescence imaging using quantum dots. Biomaterials 33:2177–2186

    Article  CAS  PubMed  Google Scholar 

  93. Deak E, Ruster B, Keller L, Eckert K, Fichtner I, Seifried E, Henschler R (2010) Suspension medium influences interaction of mesenchymal stromal cells with endothelium and pulmonary toxicity after transplantation in mice. Cytotherapy 12:260–264

    Article  CAS  PubMed  Google Scholar 

  94. Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, Bretzel RG, Elgue G, Larsson R, Nilsson B, Korsgren O (1999) Incompatibility between human blood and isolated islets of Langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes 48:1907–1914

    Article  CAS  PubMed  Google Scholar 

  95. Nilsson B, Korsgren O, Lambris JD, Ekdahl KN (2010) Can cells and biomaterials in therapeutic medicine be shielded from innate immune recognition? Trends Immunol 31:32–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Nilsson B, Ekdahl KN, Korsgren O (2011) Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant 16:620–626

    Article  CAS  PubMed  Google Scholar 

  97. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238

    Article  CAS  PubMed  Google Scholar 

  98. Stephenne X, Nicastro E, Eeckhoudt S, Hermans C, Nyabi O, Lombard C, Najimi M, Sokal E (2012) Bivalirudin in combination with heparin to control mesenchymal cell procoagulant activity. PLoS ONE 7, e42819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tatsumi K, Ohashi K, Matsubara Y, Kohori A, Ohno T, Kakidachi H, Horii A, Kanegae K, Utoh R, Iwata T, Okano T (2013) Tissue factor triggers procoagulation in transplanted mesenchymal stem cells leading to thromboembolism. Biochem Biophys Res Commun 431:203–209

    Article  CAS  PubMed  Google Scholar 

  100. Moll G, Jitschin R, von Bahr L, Rasmusson-Duprez I, Sundberg B, Lonnies L, Elgue G, Nilsson-Ekdahl K, Mougiakakos D, Lambris JD, Ringden O, Le Blanc K, Nilsson B (2011) Mesenchymal stromal cells engage complement and complement receptor bearing innate effector cells to modulate immune responses. PLoS ONE 6, e21703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Li Y, Lin F (2012) Mesenchymal stem cells are injured by complement after their contact with serum. Blood 120:3436–3443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Soland MA, Bego M, Colletti E, Zanjani ED, St Jeor S, Porada CD, Almeida-Porada G (2013) Mesenchymal stem cells engineered to inhibit complement-mediated damage. PLoS ONE 8, e60461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Quimby JM, Webb TL, Habenicht LM, Dow SW (2013) Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies. Stem Cell Res Ther 4:48

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bianco P, Barker R, Brustle O, Cattaneo E, Clevers H, Daley GQ, De Luca M, Goldstein L, Lindvall O, Mummery C, Robey PG, Sattler de Sousa EBC, Smith A (2013) Regulation of stem cell therapies under attack in Europe: for whom the bell tolls. EMBO J 32:1489–1495

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, Wang CY (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 19:35–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Alagesan S, Griffin MD (2014) Autologous and allogeneic mesenchymal stem cells in organ transplantation: what do we know about their safety and efficacy? Curr Opin Organ Transplant 19:65–72

    Article  CAS  PubMed  Google Scholar 

  107. Millard SM, Fisk NM (2013) Mesenchymal stem cells for systemic therapy: shotgun approach or magic bullets? Bioessays 35:173–182

    Article  CAS  PubMed  Google Scholar 

  108. Tolar J, Le Blanc K, Keating A, Blazar BR (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446–1455

    Article  PubMed  PubMed Central  Google Scholar 

  109. Ankrum J, Karp JM (2010) Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol Med 16:203–209

    Article  PubMed  PubMed Central  Google Scholar 

  110. Kaipe H, Carlson LM, Erkers T, Nava S, Mollden P, Gustafsson B, Qian H, Li X, Hashimoto T, Sadeghi B, Alheim M, Ringden O (2015) Immunogenicity of decidual stromal cells in an epidermolysis bullosa patient and in allogeneic hematopoietic stem cell transplantation patients. Stem Cells Dev 24:1471–1482

    Google Scholar 

  111. Crop MJ, Korevaar SS, de Kuiper R, IJzermans JN, van Besouw NM, Baan CC, Weimar W, Hoogduijn MJ (2011) Human mesenchymal stem cells are susceptible to lysis by CD8(+) T cells and NK cells. Cell Transplant 20:1547–1559

    Article  PubMed  Google Scholar 

  112. Sundin M, Ringden O, Sundberg B, Nava S, Gotherstrom C, Le Blanc K (2007) No alloantibodies against mesenchymal stromal cells, but presence of anti-fetal calf serum antibodies, after transplantation in allogeneic hematopoietic stem cell recipients. Haematologica 92:1208–1215

    Article  CAS  PubMed  Google Scholar 

  113. Schafer R, Schnaidt M, Klaffschenkel RA, Siegel G, Schule M, Radlein MA, Hermanutz-Klein U, Ayturan M, Buadze M, Gassner C, Danielyan L, Kluba T, Northoff H, Flegel WA (2011) Expression of blood group genes by mesenchymal stem cells. Br J Haematol 153:520–528

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ, Hsu SC, Smith J, Prockop DJ (2004) Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther 9:747–756

    Article  CAS  PubMed  Google Scholar 

  115. Heiskanen A, Satomaa T, Tiitinen S, Laitinen A, Mannelin S, Impola U, Mikkola M, Olsson C, Miller-Podraza H, Blomqvist M, Olonen A, Salo H, Lehenkari P, Tuuri T, Otonkoski T, Natunen J, Saarinen J, Laine J (2007) N-glycolylneuraminic acid xenoantigen contamination of human embryonic and mesenchymal stem cells is substantially reversible. Stem Cells 25:197–202

    Article  CAS  PubMed  Google Scholar 

  116. Geissler S, Textor M, Schmidt-Bleek K, Klein O, Thiele M, Ellinghaus A, Jacobi D, Ode A, Perka C, Dienelt A, Klose J, Kasper G, Duda GN, Strube P (2013) In serum veritas-in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway. Cell Death Dis 4, e970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dimmeler S, Leri A (2008) Aging and disease as modifiers of efficacy of cell therapy. Circ Res 102:1319–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Dimmeler S, Ding S, Rando TA, Trounson A (2014) Translational strategies and challenges in regenerative medicine. Nat Med 20:814–821

    Article  CAS  PubMed  Google Scholar 

  119. Efimenko AY, Kochegura TN, Akopyan ZA, Parfyonova YV (2015) Autologous stem cell therapy: how aging and chronic diseases affect stem and progenitor cells. Biores Open Access 4:26–38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kundrotas G, Gasperskaja E, Slapsyte G, Gudleviciene Z, Krasko J, Stumbryte A, Liudkeviciene R (2016) Identity, proliferation capacity, genomic stability and novel senescence markers of mesenchymal stem cells isolated from low volume of human bone marrow. Oncotarget 7:10788–10802

    PubMed  PubMed Central  Google Scholar 

  121. Caplan AI (1994) The mesengenic process. Clin Plast Surg 21:429–435

    CAS  PubMed  Google Scholar 

  122. Stolzing A, Jones E, McGonagle D, Scutt A (2008) Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 129:163–173

    Article  CAS  PubMed  Google Scholar 

  123. Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R (2000) Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp Hematol 28:707–715

    Article  CAS  PubMed  Google Scholar 

  124. Javazon EH, Beggs KJ, Flake AW (2004) Mesenchymal stem cells: paradoxes of passaging. Exp Hematol 32:414–425

    Article  CAS  PubMed  Google Scholar 

  125. Crisostomo PR, Wang M, Wairiuko GM, Morrell ED, Terrell AM, Seshadri P, Nam UH, Meldrum DR (2006) High passage number of stem cells adversely affects stem cell activation and myocardial protection. Shock 26:575–580

    Article  CAS  PubMed  Google Scholar 

  126. Binato R, de Souza Fernandez T, Lazzarotto-Silva C, Du Rocher B, Mencalha A, Pizzatti L, Bouzas LF, Abdelhay E (2013) Stability of human mesenchymal stem cells during in vitro culture: considerations for cell therapy. Cell Prolif 46:10–22

    Article  CAS  PubMed  Google Scholar 

  127. Bertolo A, Mehr M, Janner-Jametti T, Graumann U, Aebli N, Baur M, Ferguson SJ, Stoyanov JV (2016) An in vitro expansion score for tissue-engineering applications with human bone marrow-derived mesenchymal stem cells. J Tissue Eng Regen Med 10:149–161

    Google Scholar 

  128. Wagner W, Bork S, Lepperdinger G, Joussen S, Ma N, Strunk D, Koch C (2010) How to track cellular aging of mesenchymal stromal cells? Aging (Albany NY) 2:224–230

    Article  CAS  Google Scholar 

  129. Berz D, McCormack EM, Winer ES, Colvin GA, Quesenberry PJ (2007) Cryopreservation of hematopoietic stem cells. Am J Hematol 82:463–472

    Article  PubMed  PubMed Central  Google Scholar 

  130. Francois M, Copland IB, Yuan S, Romieu-Mourez R, Waller EK, Galipeau J (2012) Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing. Cytotherapy 14:147–152

    Article  CAS  PubMed  Google Scholar 

  131. Pal R, Hanwate M, Totey SM (2008) Effect of holding time, temperature and different parenteral solutions on viability and functionality of adult bone marrow-derived mesenchymal stem cells before transplantation. J Tissue Eng Regen Med 2:436–444

    Article  CAS  PubMed  Google Scholar 

  132. Otsuru S, Hofmann TJ, Raman P, Olson TS, Guess AJ, Dominici M, Horwitz EM (2015) Genomic and functional comparison of mesenchymal stromal cells prepared using two isolation methods. Cytotherapy 17:262–270

    Article  CAS  PubMed  Google Scholar 

  133. Davies OG, Smith AJ, Cooper PR, Shelton RM, Scheven BA (2014) The effects of cryopreservation on cells isolated from adipose, bone marrow and dental pulp tissues. Cryobiology 69:342–347

    Article  CAS  PubMed  Google Scholar 

  134. Pollock K, Sumstad D, Kadidlo D, McKenna DH, Hubel A (2015) Clinical mesenchymal stromal cell products undergo functional changes in response to freezing. Cytotherapy 17:38–45

    Article  PubMed  Google Scholar 

  135. Chinnadurai R, Garcia MA, Sakurai Y, Lam WA, Kirk AD, Galipeau J, Copland IB (2014) Actin cytoskeletal disruption following cryopreservation alters the biodistribution of human mesenchymal stromal cells in vivo. Stem Cell Rep 3:60–72

    Article  CAS  Google Scholar 

  136. Chinnadurai R, Copland IB, Garcia MA, Petersen C, Lewis C, Waller N, Kirk AD, Galipeau J (2016) Cryopreserved MSCs are susceptible to T-cell mediated apoptosis which is partly rescued by IFNγ licensing. Stem Cells

    Google Scholar 

  137. Cui LL, Kinnunen T, Boltze J, Nystedt J, Jolkkonen J (2016) Clumping and viability of bone marrow derived mesenchymal stromal cells under different preparation procedures: a flow cytometry-based in vitro study. Stem Cells Int 2016:1764938

    Article  PubMed  PubMed Central  Google Scholar 

  138. Morelli AE, Larregina AT (2016) Concise review: mechanisms behind apoptotic cell-based therapies against transplant rejection and graft versus host disease. Stem Cells 34:1142–1150

    Article  CAS  PubMed  Google Scholar 

  139. Saas P, Daguindau E, Perruche S (2016) Concise review: apoptotic cell-based therapies -rationale, preclinical results and future clinical developments. Stem Cells 34:1464–1473

    Google Scholar 

  140. Bruder SP, Jaiswal N, Haynesworth SE (1997) Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. J Cell Biochem 64:278–294

    Article  CAS  PubMed  Google Scholar 

  141. Gonda K, Shigeura T, Sato T, Matsumoto D, Suga H, Inoue K, Aoi N, Kato H, Sato K, Murase S, Koshima I, Yoshimura K (2008) Preserved proliferative capacity and multipotency of human adipose-derived stem cells after long-term cryopreservation. Plast Reconstr Surg 121:401–410

    Article  CAS  PubMed  Google Scholar 

  142. Liu G, Zhou H, Li Y, Li G, Cui L, Liu W, Cao Y (2008) Evaluation of the viability and osteogenic differentiation of cryopreserved human adipose-derived stem cells. Cryobiology 57:18–24

    Article  CAS  PubMed  Google Scholar 

  143. Ginis I, Grinblat B, Shirvan MH (2012) Evaluation of bone marrow-derived mesenchymal stem cells after cryopreservation and hypothermic storage in clinically safe medium. Tissue Eng Part C Methods 18:453–463

    Article  CAS  PubMed  Google Scholar 

  144. Mamidi MK, Nathan KG, Singh G, Thrichelvam ST, Mohd Yusof NA, Fakharuzi NA, Zakaria Z, Bhonde R, Das AK, Majumdar AS (2012) Comparative cellular and molecular analyses of pooled bone marrow multipotent mesenchymal stromal cells during continuous passaging and after successive cryopreservation. J Cell Biochem 113:3153–3164

    Article  CAS  PubMed  Google Scholar 

  145. Minonzio G, Corazza M, Mariotta L, Gola M, Zanzi M, Gandolfi E, De Fazio D, Soldati G (2014) Frozen adipose-derived mesenchymal stem cells maintain high capability to grow and differentiate. Cryobiology 69:211–216

    Article  PubMed  Google Scholar 

  146. Yong KW, Pingguan-Murphy B, Xu F, Abas WA, Choi JR, Omar SZ, Azmi MA, Chua KH, Wan Safwani WK (2015) Phenotypic and functional characterization of long-term cryopreserved human adipose-derived stem cells. Sci Rep 5:9596

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Luetzkendorf J, Nerger K, Hering J, Moegel A, Hoffmann K, Hoefers C, Mueller-Tidow C, Mueller LP (2015) Cryopreservation does not alter main characteristics of good manufacturing process-grade human multipotent mesenchymal stromal cells including immunomodulating potential and lack of malignant transformation. Cytotherapy 17:186–198

    Article  PubMed  Google Scholar 

  148. Cruz FF, Borg ZD, Goodwin M, Sokocevic D, Wagner D, McKenna DH, Rocco PR, Weiss DJ (2015) Freshly thawed and continuously cultured human bone marrow-derived mesenchymal stromal cells comparably ameliorate allergic airways inflammation in immunocompetent mice. Stem Cells Transl Med 4:615–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Guven S, Demirci U (2012) Integrating nanoscale technologies with cryogenics: a step towards improved biopreservation. Nanomedicine (Lond) 7:1787–1789

    Article  CAS  Google Scholar 

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Acknowledgements

Guido Moll’s contributions were made possible by German Research Foundation (DFG) funding through the Berlin-Brandenburg School for Regenerative Therapies (BSRT, GSC203); Sven Geißler was supported by grants from the Berlin-Brandenburg Center for Regenerative Therapies (BCRT), the German Federal Ministry of Education and Research (BMBF, Fkz: 01EC1402B), and the DFG (GE2512/1-2); Lech Ignatowicz was supported by the Swedish Research Council (project 2012-1883); Olle Ringdén was supported by grants from the Swedish Research Council (K2014-64X-05971-34-4), the Swedish Cancer Society (CAN2013/671), the Children’s Cancer Foundation (PR2013-0045), the Cancer Society in Stockholm (111293), and Karolinska Institutet.

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Authors and Affiliations

  1. Berlin-Brandenburg Center/School for Regenerative Therapies (BCRT/BSRT), Charité Universitätsmedizin, Berlin, Germany

    Guido Moll & Sven Geißler

  2. Therapeutic Immunology (TIM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden

    Guido Moll & Olle Ringdén

  3. Julius Wolff Institute (JWI), Berlin, Germany

    Sven Geißler

  4. Department of Nephrology and Intensive Care Medicine, Charité Universitätsmedizin, Berlin, Germany

    Rusan Catar

  5. Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden

    Lech Ignatowicz

  6. Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    Martin J. Hoogduijn

  7. Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria

    Dirk Strunk

  8. Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

    Karen Bieback

  9. German Red Cross Blood Service Baden-Württemberg – Hessen, Mannheim, Germany

    Karen Bieback

  10. Division of Therapeutic Immunology (TIM, F79), Karolinska University Hospital, SE-14186, Stockholm, Sweden

    Olle Ringdén

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Correspondence to Guido Moll .

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  1. Department of Oncology, University of Alberta, Edmonton, Alberta, Canada

    Feridoun Karimi-Busheri

  2. Department of Oncology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada

    Michael Weinfeld

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Moll, G. et al. (2016). Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?. In: Karimi-Busheri, F., Weinfeld, M. (eds) Biobanking and Cryopreservation of Stem Cells. Advances in Experimental Medicine and Biology, vol 951. Springer, Cham. https://doi.org/10.1007/978-3-319-45457-3_7

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