Abstract
Mesenchymal stromal cells (MSCs) as a pharmaceutical for ailments characterized by
pathogenic autoimmune, alloimmune and inflammatory processes now cover the spectrum
of early- to late-phase clinical trials in both industry and academic sponsored studies.
There is a broad consensus that despite different tissue sourcing and varied culture
expansion protocols, human MSC-like cell products likely share fundamental mechanisms
of action mediating their anti-inflammatory and tissue repair functionalities. Identification
of functional markers of potency and reduction to practice of standardized, easily
deployable methods of measurements of such would benefit the field. This would satisfy
both mechanistic research as well as development of release potency assays to meet
Regulatory Authority requirements for conduct of advanced clinical studies and their
eventual registration. In response to this unmet need, the International Society for
Cellular Therapy (ISCT) addressed the issue at an international workshop in May 2015
as part of the 21st ISCT annual meeting in Las Vegas. The scope of the workshop was
focused on discussing potency assays germane to immunomodulation by MSC-like products
in clinical indications targeting immune disorders. We here provide consensus perspective
arising from this forum. We propose that focused analysis of selected MSC markers
robustly deployed by in vitro licensing and metricized with a matrix of assays should
be responsive to requirements from Regulatory Authorities. Workshop participants identified
three preferred analytic methods that could inform a matrix assay approach: quantitative
RNA analysis of selected gene products; flow cytometry analysis of functionally relevant
surface markers and protein-based assay of secretome. We also advocate that potency
assays acceptable to the Regulatory Authorities be rendered publicly accessible in
an “open-access” manner, such as through publication or database collection.
Key Words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to CytotherapyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.Cytotherapy. 2006; 8: 315-317150
- MSCs: science and trials.Nat Med. 2013; 19: 812432
- Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications.Nat Immunol. 2014; 15: 1009-1016446
- MSC-based product characterization for clinical trials: an FDA perspective.Cell Stem Cell. 2014; 14: 141-145439
- Manufacturing, characterization and control of cell-based medicinal products: challenging paradigms toward commercial use.Regen Med. 2015; 10: 65-78447
- Development of a surrogate angiogenic potency assay for clinical-grade stem cell production.Cytotherapy. 2012; 14: 994-1004440
- Adult human mesenchymal stem cells added to corticosteroid therapy for the treatment of acute graft-versus-host disease.Biol Blood Marrow Transplant. 2009; 15: 804-811149
- The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria.Cytotherapy. 2015; 17: 125-127445
- Immunological characterization of multipotent mesenchymal stromal cells—the International Society for Cellular Therapy (ISCT) working proposal.Cytotherapy. 2013; 15: 1054-1061250
- Towards the creation of a standard MSC line as a calibration tool.Cytotherapy. 2015; 17: 1167-1168443
- Quantitative activation suppression assay to evaluate human bone marrow-derived mesenchymal stromal cell potency.Cytotherapy. 2015; 17: 1675448
- Mesenchymal stromal cell “licensing”: a multistep process.Leukemia. 2011; 25: 1408-1414138
- Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation.Mol Ther. 2012; 20: 187-19515
- Clinical-grade mesenchymal stromal cells produced under various good manufacturing practice processes differ in their immunomodulatory properties: standardization of immune quality controls.Stem Cells Dev. 2013; 22: 1789-18014443668498
- Mesenchymal stromal cells derived from Crohn's patients deploy indoleamine 2,3-dioxygenase mediated immune suppression, independent of autophagy.Mol Ther. 2015; 23: 1248-1261416
- Soliciting strategies for developing cell-based reference materials to advance mesenchymal stromal cell research and clinical translation.Stem Cells Dev. 2014; 23: 1157-11674414027980
- Human mesenchymal stem cells constitutively express chemokines and chemokine receptors that can be upregulated by cytokines, IFN-beta, and Copaxone.J Interferon Cytokine Res. 2007; 27: 53-64344
- Mesenchymal stem cells exhibit firm adhesion, crawling, spreading and transmigration across aortic endothelial cells: effects of chemokines and shear.PLoS ONE. 2011; 6: e256633453182247
- The involvement of CXCL11 in bone marrow-derived mesenchymal stem cell migration through human brain microvascular endothelial cells.Neurochem Res. 2014; 39: 700-706346
- Down-regulation of MHC II in mesenchymal stem cells at high IFN-gamma can be partly explained by cytoplasmic retention of CIITA.J Immunol. 2008; 180: 1826-1833347
- Inflammatory cytokine-induced intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in mesenchymal stem cells are critical for immunosuppression.J Immunol. 2010; 184: 2321-23283532881946
- The role of CCL5 in the ability of adipose tissue-derived mesenchymal stem cells to support repair of ischemic regions.Stem Cells Dev. 2014; 23: 488-5013493928761
- IFN-gamma-secreting-mesenchymal stem cells exert an antitumor effect in vivo via the TRAIL pathway.J Immunol Res. 2014; 2014: 3180983504058226
- Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype.J Immunol. 2009; 182: 7963-7973351
- Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor.Stem Cells. 2007; 25: 245-251352
- IDO-independent suppression of T cell effector function by IFN-gamma-licensed human mesenchymal stromal cells.J Immunol. 2014; 192: 1491-1501217
- Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models.Nat Neurosci. 2012; 15: 862-8703563427471
- Adoptive transfer of mesenchymal stromal cells accelerates intestinal epithelium recovery of irradiated mice in an interleukin-6-dependent manner.Cytotherapy. 2012; 14: 1164-11704
- Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy.Stem Cells. 2013; 31: 2296-2303357
- Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction.Blood. 2008; 112: 4991-499857
- Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system?.Blood. 2002; 99: 232-237386
- CCR7 guides migration of mesenchymal stem cell to secondary lymphoid organs: a novel approach to separate GvHD from GvL effect.Stem Cells. 2014; 32: 1890-1903364
- Human mesenchymal stem cells as a stable source of VEGF-producing cells.J Tissue Eng Regen Med. 2008; 2: 184-189365
- Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo.PLoS ONE. 2007; 2: e4163661855077
- Characterization of Gaucher disease bone marrow mesenchymal stromal cells reveals an altered inflammatory secretome.Blood. 2009; 114: 3181-31903682925728
- Inhibition of human mesenchymal stem cell-derived adipogenesis by the environmental contaminant benzo(a)pyrene.Toxicol in Vitro. 2009; 23: 1139-1144384
- TSG-6 released from intradermally injected mesenchymal stem cells accelerates wound healing and reduces tissue fibrosis in murine full-thickness skin wounds.J Invest Dermatol. 2014; 134: 526-537369
- Keratinocyte growth factor expression in the mesenchymal cells of human amnion.J Clin Endocrinol Metab. 1997; 82: 3319-3323370
- CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance.Nature. 2013; 495: 227-2303823600148
- Mesenchymal stem cells engineered to inhibit complement-mediated damage.PLoS ONE. 2013; 8: e604613813608620
- Immune following suppression mesenchymal stem cell transplantation in the ischemic brain is mediated by TGF-beta.Neurobiol Dis. 2013; 58: 249-257385
- Molecular trafficking mechanisms of multipotent mesenchymal stem cells derived from human bone marrow and placenta.Stem Cells Dev. 2008; 17: 929-940378
- MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines.Blood. 2007; 109: 4055-4063377
- Mesenchymal stem cells are injured by complement after their contact with serum.Blood. 2012; 120: 3436-34433763482856
- like receptors control the survival of mesenchymal stem cells.Cell Death Dis. 2013; 4: e9673753877571
- Bone marrow-derived mesenchymal stromal cells improve vascular regeneration and reduce leukocyte-endothelium activation in critical ischemic murine skin in a dose-dependent manner.Cytotherapy. 2014; 16: 1345-1360374
- A20 in inflammation and autoimmunity.Trends Immunol. 2014; 35: 22-31373
- Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-gamma licensing.Cytotherapy. 2012; 14: 147-152113279133
- TLR ligands stimulation protects MSC from NK killing.Stem Cells. 2014; 32: 290-300372
- Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2.J Cell Biochem. 2007; 101: 135-146362
- Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells.Blood. 2010; 116: 3770-3779361
- Low intensity pulsed ultrasound enhanced mesenchymal stem cell recruitment through stromal derived factor-1 signaling in fracture healing.PLoS ONE. 2014; 9: e1067223604152330
- Mesenchymal stromal cells improve survival during sepsis in the absence of heme oxygenase-1: the importance of neutrophils.Stem Cells. 2013; 31: 397-4073593572335
- Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/beta-catenin signaling.Proc Natl Acad Sci U S A. 2012; 109: E309-163583277529
- Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.Proc Natl Acad Sci U S A. 2007; 104 (PMID 17569781; 4491891813): 11002-11007
Article info
Publication history
Published online: December 23, 2015
Accepted:
November 17,
2015
Received:
November 17,
2015
Identification
Copyright
© 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
