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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?

  • Guido Moll
  • Sven Geißler
  • Rusan Catar
  • Lech Ignatowicz
  • Martin J. Hoogduijn
  • Dirk Strunk
  • Karen Bieback
  • Olle Ringdén
Part of the Advances in Experimental Medicine and Biology book series (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.

Keywords

Mesenchymal stromal cell Cell therapy Cryopreservation Freeze-thawing Freeze injury Cell engraftment Cryopreservation-induced cell death T cells Complement Coagulation 

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

Notes

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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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Guido Moll
    • 1
    • 2
  • Sven Geißler
    • 1
    • 3
  • Rusan Catar
    • 4
  • Lech Ignatowicz
    • 5
  • Martin J. Hoogduijn
    • 6
  • Dirk Strunk
    • 7
  • Karen Bieback
    • 8
    • 9
  • Olle Ringdén
    • 2
    • 10
  1. 1.Berlin-Brandenburg Center/School for Regenerative Therapies (BCRT/BSRT)Charité UniversitätsmedizinBerlinGermany
  2. 2.Therapeutic Immunology (TIM), Department of Laboratory MedicineKarolinska InstitutetStockholmSweden
  3. 3.Julius Wolff Institute (JWI)BerlinGermany
  4. 4.Department of Nephrology and Intensive Care MedicineCharité UniversitätsmedizinBerlinGermany
  5. 5.Division of Dermatology and Venereology, Department of Clinical SciencesLund UniversityLundSweden
  6. 6.Nephrology and Transplantation, Department of Internal MedicineErasmus Medical CenterRotterdamThe Netherlands
  7. 7.Experimental and Clinical Cell Therapy InstituteParacelsus Medical UniversitySalzburgAustria
  8. 8.Institute of Transfusion Medicine and Immunology, Medical Faculty MannheimHeidelberg UniversityHeidelbergGermany
  9. 9.German Red Cross Blood Service Baden-Württemberg – HessenMannheimGermany
  10. 10.Division of Therapeutic Immunology (TIM, F79)Karolinska University HospitalStockholmSweden

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