Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applications

Kim, Nayoun; Cho, Seok Goo

doi:10.1007/s12185-015-1918-6

Cited by 53 publications

(39 citation statements)

References 57 publications

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“…As already mentioned, because of the capability of MSCs to differentiate into several lineages, including chondrocytes, adipocytes and osteoblasts, as well as their role in tissue repair and their ability to home to the site of injury after systemic administration, several clinical trials for a wide range of diseases have been reported and are ongoing (Mahmood et al, 2003; Barry and Murphy, 2004; Steinert et al, 2012; Madrigal et al, 2014; Kim and Cho, 2015; Seebach et al, 2015). We extensively studied the FVV construct FV.U3-IL1RA-EGFP (NA1) compared to a FV.U3-EGFP (MD09) control vector in their ability to transduce mesenchymal cell lines and primary MSCs ( Figure 3 ) and provide sustained long-term transgene expression in primary MSCs over a time period of 137 days which is noticeable ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer

et al. 2017

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Background: Mesenchymal stem cells (MSCs) and their chondrogenic differentiation have been extensively investigated in vitro as MSCs provide an attractive source besides chondrocytes for cartilage repair therapies. Here we established prototype foamyviral vectors (FVV) that are derived from apathogenic parent viruses and are characterized by a broad host range and a favorable integration pattern into the cellular genome. As the inflammatory cytokine interleukin 1 beta (IL1β) is frequently present in diseased joints, the protective effects of FVV expressing the human interleukin 1 receptor antagonist protein (IL1RA) were studied in an established in vitro model (aggregate culture system) of chondrogenesis in the presence of IL1β.Materials and Methods: We generated different recombinant FVVs encoding enhanced green fluorescent protein (EGFP) or IL1RA and examined their transduction efficiencies and transgene expression profiles using different cell lines and human primary MSCs derived from bone marrow-aspirates. Transgene expression was evaluated by fluorescence microscopy (EGFP), flow cytometry (EGFP), and ELISA (IL1RA). For evaluation of the functionality of the IL1RA transgene to block the inhibitory effects of IL1β on chondrogenesis of primary MSCs and an immortalized MSC cell line (TERT4 cells), the cells were maintained following transduction as aggregate cultures in standard chondrogenic media in the presence or absence of IL1β. After 3 weeks of culture, pellets were harvested and analyzed by histology and immunohistochemistry for chondrogenic phenotypes.Results: The different FVV efficiently transduced cell lines as well as primary MSCs, thereby reaching high transgene expression levels in 6-well plates with levels of around 100 ng/ml IL1RA. MSC aggregate cultures which were maintained in chondrogenic media without IL1β supplementation revealed a chondrogenic phenotype by means of strong positive staining for collagen type II and matrix proteoglycan (Alcian blue). Addition of IL1β was inhibitory to chondrogenesis in untreated control pellets. In contrast, foamyviral mediated IL1RA expression rescued the chondrogenesis in pellets cultured in the presence of IL1β. Transduced MSC pellets reached thereby very high IL1RA transgene expression levels with a peak of 1087 ng/ml after day 7, followed by a decrease to 194 ng/ml after day 21, while IL1RA concentrations of controls were permanently below 200 pg/ml.Conclusion: Our results indicate that FVV are capable of efficient gene transfer to MSCs, while reaching IL1RA transgene expression levels, that were able to efficiently block the impacts of IL1β in vitro. FVV merit further investigation as a means to study the potential as a gene transfer tool for MSC based therapies for cartilage repair.

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Section: Discussionmentioning

confidence: 99%

Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer

et al. 2017

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“…Mesenchymal stem cells (MSCs) have capacity of self-renewal and multi-lineage differentiation to form mesodermal, ectodermal and endodermal tissues, including the bone, muscle, neurons, hepatocytes and skin1. MSCs can promote angiogenesis and differentiate into insulin producing cells23.…”

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confidence: 99%

Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes

Hui

Jia

et al. 2016

Sci Rep

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Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for type 1 diabetes (T1D). However, little is known on whether MSC transplantation can benefit T1D patients with ketoacidosis and its potential actions. Here, we show that infusion with bone marrow MSCs preserves β-cell function in some T1D patients with ketoacidosis by decreasing exogenous insulin requirement and increasing plasma C-peptide levels up to 1–2 years. MSC transplantation increased plasma and islet insulin contents in non-obese diabetic (NOD) mice with severe diabetes. In comparison with severe diabetes controls, MSC infusion reduced insulitis, decreased pancreatic TNF-α, and increased IL-10 and TGF-β1 expression in NOD mice. MSC infusion increased the percentages of splenic Tregs and levels of plasma IL-4, IL-10 and TGF-β1, but reduced the percentages of splenic CD8+ T and levels of plasma IFN-γ, TNF-α and IL-17A in NOD mice. Finally, infused MSCs predominantly accumulated in pancreatic tissues at 28 days post infusion. The effects of MSCs on preserving β-cell function and modulating inflammation tended to be dose-dependent and multiple doses of MSCs held longer effects in NOD mice. Hence, MSC transplantation preserved β-cell function in T1D patients and NOD mice with severe diabetes by enhancing Treg responses.

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“…Intriguingly, the in vitro pre-activation of MSCs (priming) holds promise as an interesting process for improving MSCs-immunomodulatory effects, thus conferring therapeutic advantages. However, a high diversity in the outcomes of clinical trials, using MSCs for treating different diseases, has been reported [9]. This variation remains vague since a complete mechanistic understanding of MSCs-mediated immunomodulation is still lacking.…”

Section: Introductionmentioning

confidence: 99%

Identification and Evaluation of New Immunoregulatory Genes in Mesenchymal Stromal Cells of Different Origins: Comparison of Normal and Inflammatory Conditions

Fayyad‐Kazan

Najar

Fayyad‐Kazan

et al. 2017

Med Sci Monit Basic Res

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BackgroundMesenchymal stromal cells (MSCs) possess potent immunomodulatory properties that increase their value as a cell-based therapeutic tool for managing various immune-based disorders. Over the past years, accumulated results from trials using MSCs-based therapy have shown substantial contradictions. Although the reasons underlying these discrepancies are still not completely understood, it is well known that the immunomodulatory activities mediated by distinct MSCs differ in a manner dependent on their tissue origin and adequate response to inflammation priming. Thus, characterization of new molecular pathway(s) through which distinct MSC populations can exert their immunomodulatory effects, particularly during inflammation, will undoubtedly enhance their therapeutic potential.Material/MethodsAfter confirming their compliance with ISCT criteria, quantitative real time-PCR (qRT-PCR) was used to screen new immunoregulatory genes in MSCs, derived from adipose tissue, foreskin, Wharton’s jelly or the bone-marrow, after being cultivated under normal and inflammatory conditions.ResultsFGL2, GAL, SEMA4D, SEMA7A, and IDO1 genes appeared to be differentially transcribed in the different MSC populations. Moreover, these genes were not similarly modulated following MSCs-exposure to inflammatory signals.ConclusionsOur observations suggest that these identified immunoregulatory genes may be considered as potential candidates to be targeted in order to enhance the immunomodulatory properties of MSCs towards more efficient clinical use.

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Overcoming immunoregulatory plasticity of mesenchymal stem cells for accelerated clinical applications

Abstract: we discuss novel strategic approaches that enhance the therapeutic potential of MSCs through a consideration of MSC plasticity in immune modulation.

Cited by 53 publications

References 57 publications

Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer

Rescued Chondrogenesis of Mesenchymal Stem Cells under Interleukin 1 Challenge by Foamyviral Interleukin 1 Receptor Antagonist Gene Transfer

Infusion with Human Bone Marrow-derived Mesenchymal Stem Cells Improves β-cell Function in Patients and Non-obese Mice with Severe Diabetes

Identification and Evaluation of New Immunoregulatory Genes in Mesenchymal Stromal Cells of Different Origins: Comparison of Normal and Inflammatory Conditions

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