MSC-Based Product Characterization for Clinical Trials: An FDA Perspective

Mendicino, Michael; Bailey, Alexander M.; Wonnacott, Keith; Puri, Raj K.; Bauer, Steven R.

doi:10.1016/j.stem.2014.01.013

Cited by 410 publications

(332 citation statements)

References 11 publications

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“…A major contributor to these inconsistent clinical outcomes may be the inherent variability in the immunosuppressive capacity of MSC lines due to differing tissues of origin, manufacturing processes, and donor-specific differences (10,(21)(22)(23). Although this functional heterogeneity is well known, no reliable predictors of MSC immunosuppressive capacity have been identified (3,24).…”

Section: Morphological Features Of Mscs After Ifn-γ Stimulation Corrementioning

confidence: 99%

“…Efforts have been made to identify MSC quality attributes associated with immunosuppression (6,7), but the majority of clinical studies (10) rely upon the surface markers described by Dominici et al (11). Having previously shown that morphology can predict MSC mineralization capacity (12), we hypothesized that morphological features associated with immunosuppression in MSCs could be identified and used to predict their performance in our quantitative immunosuppression assay.…”

mentioning

confidence: 99%

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Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

Klinker

Marklein

Surdo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

158

166

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Human mesenchymal stromal cell (MSC) lines can vary significantly in their functional characteristics, and the effectiveness of MSCbased therapeutics may be realized by finding predictive features associated with MSC function. To identify features associated with immunosuppressive capacity in MSCs, we developed a robust in vitro assay that uses principal-component analysis to integrate multidimensional flow cytometry data into a single measurement of MSC-mediated inhibition of T-cell activation. We used this assay to correlate single-cell morphological data with overall immunosuppressive capacity in a cohort of MSC lines derived from different donors and manufacturing conditions. MSC morphology after IFN-γ stimulation significantly correlated with immunosuppressive capacity and accurately predicted the immunosuppressive capacity of MSC lines in a validation cohort. IFN-γ enhanced the immunosuppressive capacity of all MSC lines, and morphology predicted the magnitude of IFN-γ-enhanced immunosuppressive activity. Together, these data identify MSC morphology as a predictive feature of MSC immunosuppressive function.H uman mesenchymal stromal cells (MSCs) can potently suppress immune responses in vitro and in animal models of human disease (1, 2), but to date MSC-based therapies have produced mixed results in clinical trials for treatment of inflammatory and autoimmune diseases (3, 4). A major challenge in the development of consistently effective MSC-based immunosuppressive therapies is that MSC lines derived from different donors and manufacturing processes (i.e., cell expansion) can possess markedly dissimilar immunosuppressive function (3,5,6). Although methods exist to assess MSC immunosuppression in vitro, they are often based on only a few measured outcomes, assay culture conditions, and donor MSC samples (5, 7-9). To improve upon these methods, we developed an experimental and analytical approach to quantify MSC-mediated immune suppression using principal-component analysis (PCA) to integrate multiple measurements of T-cell activation assessed at a range of MSC densities. This approach allowed us to determine a single value for immunosuppressive capacity for MSC lines derived from two different manufacturing processes and 13 independent donors.Another major challenge associated with MSC-based immune therapies is the lack of well-defined predictive markers to identify MSC lines with therapeutically relevant biological activities or manufacturing processes that produce more effective MSCbased products. Efforts have been made to identify MSC quality attributes associated with immunosuppression (6, 7), but the majority of clinical studies (10) rely upon the surface markers described by Dominici et al. (11). Having previously shown that morphology can predict MSC mineralization capacity (12), we hypothesized that morphological features associated with immunosuppression in MSCs could be identified and used to predict their performance in our quantitative immunosuppression assay.Using our quantitative method for as...

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Section: Morphological Features Of Mscs After Ifn-γ Stimulation Corrementioning

confidence: 99%

mentioning

confidence: 99%

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

Klinker

Marklein

Surdo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

158

166

View full text Add to dashboard Cite

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“…In this study, all culture in F1, F2, and F3 medium showed positive mesenchymal stem cell markers, which all were above 90%, except expressions of CD73 that were all above 80%, which was in accordance to the requirements of MSC-based product as Investigational New Drug Applications (INDs) for clinical trials. 32 According to Mendicino et al,32 for clinical trials, the minimum range of expression levels of CD105, CD90, and CD73 should be above 80% and thus, our results were still corresponding with the MSC criteria for clinical trial.…”

Section: Discussionmentioning

confidence: 54%

“…Negative surface marker expressions of hADSC that were expanded in F1, F2, and F3 medium were also still in range of MSC-Based Product INDs for clinical trials, 32 and minimal criteria of MSC proposed by ISCT. 31 Almost all earlier studies confirmed that platelet lysate as FBS substitute was a good supplement in culture media.…”

Section: Discussionmentioning

confidence: 91%

A Proliferation and surface marker characterization of adipose stem cells after culture in various processed outdated platelet lysate containing media

Sari¹,

Luviah²,

Purwoko³

et al. 2017

IJPTR

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: Human adipose derived stem cells (hADSCs) can be cultured in outdated platelet lysate (PL) containing medium. Processing of thrombocyte concentrate to get PL can be done by various freeze-thaw cycles. There was no information whether various processed PL containing media gave the same proliferation potential and surface marker expressions. Therefore, the aim of this study was to know the proliferation and surface marker characteristics of hADSCs after expansion in various processed PL containing media. hADCSs were cultured in various processed PL containing media, namely F1, F2, and F3, where the numbers denoted once, twice and three times freeze-thaw cycles. Proliferations were measured on day-2, day-4, day-7, and day-10. Positive surface markers were CD90, CD73, and CD105, while negative markers were a cocktail of CD34, CD45, CD11b, CD19, and HLA-DR. Difference in proliferations and surface marker expressions between F1, F2, and F3 were analyzed by one-way ANOVA. We found that cell proliferation in F1, F2, and F3 showed no significant difference on day-7 and day-10. The expression levels of CD90 and CD 105 in F1, F2, and F3 were all above 90%, which correspond with mesenchymal stem cells according to the requirement of International Society for Cell Therapy (ISCT). However, CD73 showed highest (97%) expression on F2 and lowest on F3 (81.8%). Negative marker range was 2.4-2.9%. In Conclusion, at the end of culture, hADSCs showed similar profile and proliferation, when cultured in F1, F2, and F3.

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“…Bone tissue in the clinic Review others), angiogenic (PDGF, VEGF, among others), inflammation-control (TNFα, interleukins, interferon-γ, among others) and systemic factors (Vitamin D, growth hormone, calcitonin, parathyroid hormone, among others) [44][45][46][47]. These cell signaling molecules have been studied extensively in the laboratory but few have been used in therapies that have gone through clinical trials.…”

Section: Bmp-2mentioning

confidence: 99%

The Potential Impact of Bone Tissue Engineering in the Clinic

et al. 2016

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Bone tissue engineering (BTE) intends to restore structural support for movement and mineral homeostasis, and assist in hematopoiesis and the protective functions of bone in traumatic, degenerative, cancer, or congenital malformation. While much effort has been put into BTE, very little of this research has been translated to the clinic. In this review, we discuss current regenerative medicine and restorative strategies that utilize tissue engineering approaches to address bone defects within a clinical setting. These approaches involve the primary components of tissue engineering: cells, growth factors and biomaterials discussed briefly in light of their clinical relevance. This review also presents upcoming advanced approaches for BTE applications and suggests a probable workpath for translation from the laboratory to the clinic.

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MSC-Based Product Characterization for Clinical Trials: An FDA Perspective

Cited by 410 publications

References 11 publications

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity

A Proliferation and surface marker characterization of adipose stem cells after culture in various processed outdated platelet lysate containing media

The Potential Impact of Bone Tissue Engineering in the Clinic

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