Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion

Zimmermann, J.; McDevitt, Todd C.

doi:10.1016/j.jcyt.2013.09.004

Cited by 149 publications

(174 citation statements)

References 68 publications

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“…It is known that IFN-γ treatment of MSCs for 4 days leads to an increase in the IL-6 expression level [66]. In our experiments, MSC priming with IFN-γ did not affect the REL of IL-6 ( Figure 7C).…”

Section: Il-6 Expressionsupporting

confidence: 42%

Alterations of Multipotent Mesenchymal Stromal Cells Induced by Interaction with Allogeneic Lymphocytes In Vitro

NM¹,

Nj²

2017

IJST

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Section: Il-6 Expressionsupporting

confidence: 42%

Alterations of Multipotent Mesenchymal Stromal Cells Induced by Interaction with Allogeneic Lymphocytes In Vitro

NM¹,

Nj²

2017

IJST

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“…We also evaluated the angiogenic characteristics of thymus MSCs using an established 3D sprouting assay [41][42][43] because 3D culture is known to enhance the regenerative abilities of MSCs and more closely approximates the in vivo setting [44][45][46][47]. In multicellular spheroids, HUVECs and thymus MSCs are in a 3D, highcell-density aggregate during initial formation, facilitating direct contact and paracrine cell interactions.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Angiogenic Potential of Human Neonatal and Infant Thymus Mesenchymal Stromal Cells

Wang

Mundada

Johnson

et al. 2015

Stem Cells Translational Medicine

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Mesenchymal stromal cells (MSCs) are present in large numbers in discarded neonatal and infant thymus tissue and can be isolated by an explant culture method. Explant culture‐isolated thymus MSCs demonstrate the classical characteristics of bone marrow MSCs. Thymus MSCs also possess proangiogenic qualities and deserve further consideration as a potential cell therapeutic agent to promote tissue regeneration and repair and for use in strategies to vascularize engineered tissues.

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“…In other cell types (HepG2 and HeLa), differences in cell adhesion signaling (drug and matrix-induced) that led to adoption of distinct morphologies were discovered to significantly impact IFN-γ signaling as actin cytoskeletal arrangement was directly linked to STAT1 dephosphorylation (35). This suggests that morphology not only serves as a phenotypic readout for IFN-γ treatment, but could also play a direct role in the magnitude of the MSC immunosuppression response as IFN-γ signaling promotes production of immunomodulatory factors such as indoleamine 2,3-dioxygenase, prostaglandin E 2 , and IL-6 (20,36,37).…”

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

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.

168

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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Pre-conditioning mesenchymal stromal cell spheroids for immunomodulatory paracrine factor secretion

Cited by 149 publications

References 68 publications

Alterations of Multipotent Mesenchymal Stromal Cells Induced by Interaction with Allogeneic Lymphocytes In Vitro

Alterations of Multipotent Mesenchymal Stromal Cells Induced by Interaction with Allogeneic Lymphocytes In Vitro

Characterization and Angiogenic Potential of Human Neonatal and Infant Thymus Mesenchymal Stromal Cells

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

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