Immunomodulatory Properties of Induced Pluripotent Stem Cell‐Derived Mesenchymal Cells

Ng, Joseph Kim Fai; Hynes, Kim; White, Gregory; Sivanathan, Kisha Nandini; Vandyke, Kate; Bartold, P. Mark; Gronthos, Stan

doi:10.1002/jcb.25596

Cited by 41 publications

(40 citation statements)

References 71 publications

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“…While derivation of ESC‐MSCs was first reported in 2005 and demonstration of immunomodulation has been consistent for this type of PSC‐derived MSCs , studies on iPSC‐MSC immunomodulation have been few and discrepant. The most consistent immunomodulatory findings for iPSC‐MSCs are found in in vivo disease model studies, which demonstrate that these MSCs modulate CD4 T cells toward a Treg phenotype; however, effects on IFN‐γ, a cytokine representing effector Th1, was inconsistent and dependent on the disease model used . In vitro studies showed even less consistent results, with one study demonstrating strong immunomodulation toward natural killer lymphocytes whereas another study did not find any immunomodulatory effects .…”

Section: Discussionmentioning

confidence: 81%

“…Strikingly, the latter study used a less standard experimental procedure of adding IL‐2, a potent T cell mitogen, to its PBMC stimulation protocol. Overall, iPSC‐MSC immunomodulation studies suffer from either use of few cell lines with little diversity in cell‐of‐origin used and reprogramming methods , as well as lack of direct comparison with other types of MSCs, including tissue‐source MSCs and ESC‐MSCs. In including iPSC‐MSCs of diverse cell‐of‐origin and reprogramming protocols along with direct comparison with two lines of ESC‐MSCs and multiple donors of BM‐MSCs, our report clearly demonstrate that iPSC‐MSCs are immunomodulatory toward T lymphocytes, suppressing Th1/Th17 and promoting Treg responses to an extent which is comparable to other well‐studied sources of human MSCs.…”

Section: Discussionmentioning

confidence: 99%

“…MSCs derived from human ESCs (ESC‐MSCs) were the first to be reported on, and with the exception of one study in which only one cell line was used , nearly all studies have found significant immunomodulatory effects for these MSCs . On the other hand, data on iPSC‐MSC immunomodulation have ranged from immunosuppression to no effect , to immunoreactive . Unlike ESCs, iPSCs can be artificially generated from any somatic cell sources using many methods, but cell‐of‐origin differences can result in alterations in differentiation capacity .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Wang

Jiang²,

Ting

et al. 2018

Stem Cells

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Multilineage tissue-source mesenchymal stem cells (MSCs) possess strong immunomodulatory properties and are excellent therapeutic agents, but require constant isolation from donors to combat replicative senescence. The differentiation of human induced pluripotent stem cells (iPSCs) into MSCs offers a renewable source of MSCs; however, reports on their immunomodulatory capacity have been discrepant. Using MSCs differentiated from iPSCs reprogrammed using diverse cell types and protocols, and in comparison to human embryonic stem cell (ESC)-MSCs and bone marrow (BM)-MSCs, we performed transcriptome analyses and assessed for functional immunomodulatory properties. Differentiation of MSCs from iPSCs results in decreased c-Myc expression and its downstream pathway along with a concomitant downregulation in the DNA replication pathway. All four lines of iPSC-MSCs can significantly suppress in vitro activated human peripheral blood mononuclear cell (PBMC) proliferation to a similar degree as ESC-MSCs and BM-MSCs, and modulate CD4 T lymphocyte fate from a type 1 helper T cell (Th1) and IL-17A-expressing (Th17) cell fate to a regulatory T cell (Treg) phenotype. Moreover, iPSC-MSCs significantly suppress cytotoxic CD8 T proliferation, activation, and differentiation into type 1 cytotoxic T (Tc1) and IL-17-expressing CD8 T (Tc17) cells. Coculture of activated PBMCs with human iPSC-MSCs results in an overall shift of secreted cytokine profile from a pro-inflammatory environment to a more immunotolerant milieu. iPSC-MSC immunomodulation was also validated in vivo in a mouse model of induced inflammation. These findings support that iPSC-MSCs possess low oncogenicity and strong immunomodulatory properties regardless of cell-of-origin or reprogramming method and are good potential candidates for therapeutic use. Stem Cells 2018;36:903-914.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Wang

Jiang²,

Ting

et al. 2018

Stem Cells

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“…To avoid long in vitro culturing for the generation of high JPC numbers and the associated cell senescence, induced pluripotent stem cells (iPSCs) might serve as an alternative source of MSCs because of their unlimited self-renewal capacity and differentiation potential [7]. A variety of methods has been published to differentiate iPSCs into iPSC-derived mesenchymal stem/stromal-like cells (iMSCs), demonstrating comparable properties of MSCs and iMSCs regarding morphology, marker expression, differentiation potential, or immunomodulatory properties [8,9].…”

Section: Introductionmentioning

confidence: 99%

iPSC-Derived MSCs Versus Originating Jaw Periosteal Cells: Comparison of Resulting Phenotype and Stem Cell Potential

Umrath

Weber

Reinert

et al. 2020

IJMS

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Induced pluripotent stem cell-derived mesenchymal stem cell-like cells (iMSCs) are considered to be a promising source of progenitor cells for approaches in the field of bone regeneration. In a previous study, we described the generation of footprint-free induced pluripotent stem cells (iPSCs) from human jaw periosteal cells (JPCs) by transfection of a self-replicating RNA (srRNA) and subsequent differentiation into functional osteogenic progenitor cells. In order to facilitate the prospective transfer into clinical practice, xeno-free reprogramming and differentiation methods were established. In this study, we compared the properties and stem cell potential of the iMSCs produced from JPC-derived iPSCs with the parental primary JPCs they were generated from. Our results demonstrated, on the one hand, a comparable differentiation potential of iMSCs and JPCs. Additionally, iMSCs showed significantly longer telomere lengths compared to JPCs indicating rejuvenation of the cells during reprogramming. On the other hand, proliferation, mitochondrial activity, and senescence-associated beta-galactosidase (SA-β-gal) activity indicated early senescence of iMSCs. These data demonstrate the requirement of further optimization strategies to improve mesenchymal development of JPC-derived iPSCs in order to take advantage of the best features of reprogrammed and rejuvenated cells.

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“…Periodontal tissue has Tr1-like T-cells-a type of Treg recently described patrolling peripheral tissue [22]. Similarly, it has been reported that the presence of PDL-MSCs and G-MSCs in co-cultures with activated PBMCs increases the CD4 + CD25 + Foxp3 + population and suppresses T-cell effector cells, as with Th1/Th2/Th17 populations [63]. Paradoxically, it has been reported that G-MSCs in vitro are not capable of generating Tregs; however, after their application in an acute GVHD model, high levels of Foxp3 expression were detected, along with a reduction in the levels of proinflammatory cytokines IL-17 and IFNγ and an increase in IL-2 levels, the role of which is important for the differentiation of induced regulatory T-cells (iTregs), supporting the suppressor function of CD4 iTregs under inflammatory conditions [64].…”

Section: Discussionmentioning

confidence: 85%

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

Rosa-Ruiz

Álvarez-Pérez

Cortés-Morales

et al. 2019

Cells

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Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory properties and have been used as immune regulators for the treatment of graft-versus-host disease (GVHD). Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to BM-MSCs for potential clinical applications because of their accessibility and easy preparation. The aim of this in vitro study was to compare MSCs from dental pulp (DP-MSCs), gingival tissue (G-MSCs), and periodontal ligament (PDL-MSCs) in terms of their immunosuppressive properties against lymphoid cell populations enriched for CD3+ T cells to determine which MSCs would be the most appropriate for in vivo immunoregulatory applications. BM-MSCs were included as the gold standard. Our results demonstrated, in vitro, that MSCs from DP, G, and PDL showed immunoregulatory properties similar to those from BM, in terms of the cellular proliferation inhibition of both CD4+- and CD8+-activated T-cells. This reduced proliferation in cell co-cultures correlated with the production of interferon-γ and tumor necrosis factor alpha (TNF-α) and the upregulation of programmed death ligand 1 (PD-L1) in MSCs and cytotoxic T-cell-associated Ag-4 (CTLA-4) in T-cells and increased interleukin-10 and prostaglandin E2 production. Interestingly, we observed differences in the production of cytokines and surface and secreted molecules that may participate in T-cell immunosuppression in co-cultures in the presence of DT-MSCs compared with BM-MSCs. Importantly, MSCs from four sources favored the generation of T-cell subsets displaying the regulatory phenotypes CD4+CD25+Foxp3+ and CD4+CD25+CTLA-4+. Our results in vitro indicate that, in addition to BM-MSCs, MSCs from all of the dental sources analyzed in this study might be candidates for future therapeutic applications.

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Immunomodulatory Properties of Induced Pluripotent Stem Cell‐Derived Mesenchymal Cells

Cited by 41 publications

References 71 publications

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

Differentiation of Mesenchymal Stem Cells from Human Induced Pluripotent Stem Cells Results in Downregulation of c-Myc and DNA Replication Pathways with Immunomodulation Toward CD4 and CD8 Cells

iPSC-Derived MSCs Versus Originating Jaw Periosteal Cells: Comparison of Resulting Phenotype and Stem Cell Potential

Mesenchymal Stem/Stromal Cells Derived from Dental Tissues: A Comparative In Vitro Evaluation of Their Immunoregulatory Properties Against T cells

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