title: Cryopreserved or Fresh Mesenchymal Stromal Cells: Only a Matter of Taste or Key to Unleash the Full Clinical Potential of MSC Therapy?
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.
authors.affiliation: Berlin-Brandenburg Center/School for Regenerative Therapies (BCRT/BSRT), Charité Universitätsmedizin, Berlin, Germany. guido.moll@charite.se.|Therapeutic Immunology (TIM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. guido.moll@charite.se.
authors.forename: Guido
authors.initials: G
authors.lastname: Moll
authors.affiliation: Berlin-Brandenburg Center/School for Regenerative Therapies (BCRT/BSRT), Charité Universitätsmedizin, Berlin, Germany.|Julius Wolff Institute (JWI), Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Geißler
authors.affiliation: Department of Nephrology and Intensive Care Medicine, Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.affiliation: Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Lech
authors.initials: L
authors.lastname: Ignatowicz
authors.affiliation: Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hoogduijn
authors.affiliation: Experimental and Clinical Cell Therapy Institute, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Strunk
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.|German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Bieback
authors.affiliation: Therapeutic Immunology (TIM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Division of Therapeutic Immunology (TIM, F79), Karolinska University Hospital, SE-14186, Stockholm, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Ringdén
mesh_terms: D018070:Biological Specimen Banks / Q000706:statistics & numerical data*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002478:Cells, Cultured; D015925:Cryopreservation / Q000379:methods*; D003451:Cryoprotective Agents / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D006085:Graft Survival; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D003451:Cryoprotective Agents; D016207:Cytokines; D007155:Immunologic Factors
keywords: Cell engraftment; Cell therapy; Coagulation; Complement; Cryopreservation; Cryopreservation-induced cell death; Freeze injury; Freeze-thawing; Mesenchymal stromal cell; T cells