Prevention of acute liver allograft rejection by IL-10-engineered mesenchymal stem cells

Niu, Junfeng; Yue, Wen; Song, Yangyang; Zhang, Y.; Qi, Xin; Wang, Z.; Liu, B.; Shen, Hongxing; Hu, Xiaolei

doi:10.1111/cei.12283

Cited by 48 publications

(39 citation statements)

References 41 publications

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“…In a rat liver transplant model, prominent suppressive effects of MSCs were observed in many studies; however, the exact mechanism is not fully clear [2]. Moreover, although the ability of MSCs to provide immunological support during liver transplants has been described, whether the promotion of liver transplant tolerance by MSCs differs in the context of other solid organ transplants remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Although profound immunosuppression of MSCs has been clearly observed in rat liver transplantations, the precise mechanism remains unclear [2]. Previous studies have primarily focused on the interaction of MSCs with dendritic cells (DC), natural killer (NK) cells, and T cells, whereas another important type of immune cell, macrophages, has not received much attention [3].…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance

et al. 2015

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The role of mesenchymal stromal cells (MSCs) in the modulation of liver transplant tolerance has attracted significant interest. However, the interaction between MSCs and Kupffer cells (KCs) has received little attention, and the effect of this interaction on liver transplant tolerance remains unclear. KCs were cultured in the presence and absence of MSCs. After 24 h, cells were treated with lipopolysaccharide (LPS), after which the production of cytokines and the expression of surface antigens were measured for cell function identification. Moreover, the effects of the KCs and the prostaglandin E2 (PGE2) levels produced by the MSCs were determined using an experimental rat liver transplantation model. Blood and liver samples were collected at three time points after transplantation for further analysis. After LPS treatment, when compared with the KC single cultures, the expression of pro-inflammatory cytokines (IL-1β, IL-6, MHC-II, CD40, CD80, and CD86) in the coculture system was down-regulated, whereas the expression of anti-inflammatory cytokines (TGF-β, IL-4, PGE2, and IL-10) was markedly increased. These data indicate that MSCs can reprogram the phenotype of KCs. However, KCs treated with miR/TNF-α (tumor necrosis factor) plasmid prior to coculture to inhibit the production of TNF-α resulted in an inhibition of the reprogramming effect of MSCs. Moreover, overexpression of PGE2 in MSCs increased the effect of MSCs on KC reprogramming. After rat liver transplantation, allograft recipients that received MSCs showed better allograft tolerance when compared with rats in which KC function was inhibited. Furthermore, rats treated with MSCs overexpressing PGE2 demonstrated the best liver tolerance of all of the groups tested. MSCs reprogram the phenotype of KCs through TNF-α and PGE2, and this process is crucial for the immunomodulatory function of MSCs in liver transplantation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance

et al. 2015

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“…Compared with placebo, intravenous injection of syngeneic IL-10-transduced MSCs 30 min after transplantation resulted in longer survival, lower Banff scores, increased expres sion of the Treg-associated cytokines IL-10 and TGF-β1, and the transcription factor FOXP3, as well as decreased expression of T helper (Th)17 T-cell-related cytokines IL-17, IL-6, interferon-γ, tumor necrosis factor-α, and IL-23 and the retinoic-acid related orphan receptor gamma (RORγ) transcription factor (RORγt) [57]. RORγ is a protein that in humans is encoded by the RORC (RAR-related orphan receptor C) gene.…”

Section: Animal Studiesmentioning

confidence: 99%

The use of mesenchymal stromal cells in solid organ transplantation

Delens

Jouret

Detry

et al. 2016

The Biology and Therapeutic Application of Mesenchymal Cells

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“…For instance, the expression of anti-inflammatory cytokines, such as IL-10 was achieved in BM-MSCs [24] and ASCs [222,270] and IL-4 in BM-MSCs [271]. Curiously, in BM-MSCs transfected with pro-inflammatory TNF-α, an immunosuppressive activation was observed [272].…”

Section: Other Applicationsmentioning

confidence: 99%

Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine

Nowakowski

Walczak

Janowski

et al. 2015

Stem Cells and Development

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Mesenchymal stem cells (MSCs), which can be obtained from various organs and easily propagated in vitro, are one of the most extensively used types of stem cells and have been shown to be efficacious in a broad set of diseases. The unique and highly desirable properties of MSCs include high migratory capacities toward injured areas, immunomodulatory features, and the natural ability to differentiate into connective tissue phenotypes. These phenotypes include bone and cartilage, and these properties predispose MSCs to be therapeutically useful. In addition, MSCs elicit their therapeutic effects by paracrine actions, in which the metabolism of target tissues is modulated. Genetic engineering methods can greatly amplify these properties and broaden the therapeutic capabilities of MSCs, including transdifferentiation toward diverse cell lineages. However, cell engineering can also affect safety and increase the cost of therapy based on MSCs; thus, the advantages and disadvantages of these procedures should be discussed. In this review, the latest applications of genetic engineering methods for MSCs with regenerative medicine purposes are presented.

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Prevention of acute liver allograft rejection by IL-10-engineered mesenchymal stem cells

Abstract: SummaryHepatic allograft rejection remains a challenging problem, with acute rejection episode as the major barrier for long-term survival in liver transplant recipients. To explore a strategy to prevent allograft rejection, we hypothesized that mesenchymal stem cells (

Cited by 48 publications

References 41 publications

Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance

Mesenchymal stromal cell-dependent reprogramming of Kupffer cells is mediated by TNF-α and PGE2 and is crucial for liver transplant tolerance

The use of mesenchymal stromal cells in solid organ transplantation

Genetic Engineering of Mesenchymal Stem Cells for Regenerative Medicine

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