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1.
Int Immunopharmacol ; 125(Pt A): 111096, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37871378

ABSTRACT

BACKGROUND: Mesenchymal stromal cells (MSCs) show great potential for immunomodulatory and anti-inflammatory treatments. Clinical trials have been performed for the treatment of Type 1 diabetes, graft-versus-host disease and organ transplantation, which offer a promise of MSCs as an immunomodulatory therapy. Nevertheless, their unstable efficacy and immunogenicity concerns present challenges to clinical translation. It has emerged that the MSC-derived secretome, which includes secreted proteins, exosomes, apoptotic bodies (ABs) and other macromolecules, may have similar therapeutic effects to parent MSCs. Among all of the components of the MSC-derived secretome, most interest thus far has been garnered by exosomes for their therapeutic potential. However, since MSCs were reported to undergo apoptosis after in vivo transplantation and release ABs, we speculated as to whether ABs have immunomodulatory effects. In this study, cytokine licensing was used to enhance the immunomodulatory potency of MSCs and ABs derived from licensed MSCs in vitro were isolated to explore their immunomodulatory effects as an effective non-viable cell therapy. RESULTS: IFN-γ and IFN-γ/TGF-ß1 licensing enhanced the immunomodulatory effect of MSCs on T cell proliferation. Further, TGF-ß1 and IFN-γ licensing strengthened the immunomodulatory effect of MSC on reducing the TNF-α and IL-1ß expression by M1 macrophage-like THP-1 cells. Additionally, we discovered the immunomodulatory effect mediated by MSC-derived apoptotic bodies. Licensing impacted the uptake of ABs by recipient immune cells and importantly altered their phenotypes. CONCLUSION: ABs derived from IFN-γ/TGF-ß1-licensed apoptotic MSCs significantly inhibited T cell proliferation, induced more regulatory T cells, and maintained immunomodulatory T cells but reduced pro-inflammatory T cells.


Subject(s)
Exosomes , Mesenchymal Stem Cells , Humans , Transforming Growth Factor beta1/metabolism , Cells, Cultured , Bone Marrow , Immunomodulation , Exosomes/metabolism , Mesenchymal Stem Cells/metabolism
2.
Pharmacol Res ; 172: 105833, 2021 10.
Article in English | MEDLINE | ID: mdl-34418563

ABSTRACT

An emerging strategy is needed to treat autoimmune diseases, many of which are chronic with no definitive cure. Current treatments only alleviate symptoms and have many side effects affecting patient quality of life. Recently, nanoparticle drug delivery systems, an emerging method in medicine, has been used to target cells or organs, without damaging normal tissue. This approach has led to fewer side effects, along with a strong immunosuppressive capacity. Therefore, a nanotechnology approach may help to improve the treatment of autoimmune diseases. In this review, we separated nanoparticles into three categories: synthesized nanoparticles, biomimetic nanoparticles, and extracellular vesicles. This review firstly compares the typical mechanism of action of these three nanoparticle categories respectively in terms of active targeting, camouflage effect, and similarity to parent cells. Then their immunomodulation properties are discussed. Finally, the challenges faced by all these nanoparticles are described.


Subject(s)
Autoimmune Diseases/drug therapy , Biomimetics , Extracellular Vesicles , Nanoparticles/administration & dosage , Animals , Drug Delivery Systems , Humans , Immunomodulation , Nanoparticles/chemistry
3.
Stem Cell Res Ther ; 12(1): 227, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33823917

ABSTRACT

BACKGROUND: Systemic administration of mesenchymal stromal cells (MSCs) has been efficacious in many inflammatory disease settings; however, little data are available on the potential immunomodulatory effects following local MSC administration in the context of corneal transplantation. The purpose of this study was to assess the potential of subconjunctival injection of MSCs to promote corneal allograft survival. METHODS: MSCs were isolated from female C57BL/6 (H-2k) or Balb/c (H-2d) mice and extensively characterized. An allogeneic mouse corneal transplant model was used with Balb/c mice as recipients of C57BL/6 grafts. A dose-finding study starting with 5 × 105 MSCs injected subconjunctivally at day - 7 was tested first followed by a more clinically translatable low-dose single or dual injection strategy on day - 1 and day + 1 before/after transplantation. Graft transparency served as the primary indicator of transplant rejection while neovascularization was also recorded. Lymphocytes (from draining lymph nodes) and splenocytes were isolated from treatment groups on day 2 post-transplantation and characterized by flow cytometry and qRT-PCR. RESULTS: Both high- and low-dose injection of allogeneic MSCs on day - 7 led to 100% graft survival over the observation period. Moreover, low-dose dual subconjunctival injection of 5 × 104 allogeneic MSCs on day - 1 or day + 1 led to 100% allograft survival in transplant recipients (n = 7). We also demonstrate that single administration of allogeneic MSCs on either day - 1 or day + 1 promotes rejection-free graft survival in 100% (n = 8) and 86% (n = 7) of transplanted mice, respectively. Early time point ex vivo analysis suggests modulation of innate immune responses towards anti-inflammatory, pro-repair responses by local MSC administration. CONCLUSION: This work demonstrates that low-dose subconjunctival injection of allogeneic MSCs successfully promotes corneal allograft survival and may contribute to refining future MSC immunotherapies for prevention of corneal allograft rejection.


Subject(s)
Corneal Transplantation , Hematopoietic Stem Cell Transplantation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Animals , Female , Graft Rejection/prevention & control , Graft Survival , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
4.
Mol Ther ; 28(9): 2023-2043, 2020 09 02.
Article in English | MEDLINE | ID: mdl-32531237

ABSTRACT

Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-ß1 (TGF-ß MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-ß MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-ß MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-ß MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-ß MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-ß MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-ß1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.


Subject(s)
Allografts/immunology , Corneal Transplantation/adverse effects , Graft Rejection/immunology , Graft Rejection/therapy , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/drug effects , Transforming Growth Factor beta1/pharmacology , Animals , Cells, Cultured , Coculture Techniques/methods , Culture Media, Conditioned , Female , Graft Survival/immunology , Immune Tolerance/drug effects , Lymphocyte Activation/immunology , Mesenchymal Stem Cells/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Models, Animal , Recombinant Proteins/pharmacology , T-Lymphocytes, Regulatory/immunology , Transplantation, Homologous/methods , Treatment Outcome
5.
Stem Cells ; 36(8): 1210-1215, 2018 08.
Article in English | MEDLINE | ID: mdl-29726063

ABSTRACT

Mesenchymal stem/stromal cells (MSC) are an immunomodulatory cell population which are under preclinical and clinical investigation for a number of inflammatory conditions including transplantation. In this study, a well-established rat corneal transplantation model was used to test the ability of human MSC to prolong corneal allograft rejection-free survival using a pre-transplant intravenous infusion protocol previously shown to be efficacious with allogeneic rat MSC. Surprisingly, pre-transplant administration of human MSC had no effect on corneal allograft survival. In vitro, human MSC failed to produce nitric oxide and upregulate IDO and, as a consequence, could not suppress rat T-cell proliferation. Furthermore, human MSC were not activated by rat pro-inflammatory cytokines. Thus, interspecies incompatibility in cytokine signaling leading to failure of MSC licensing may explain the lack of in vivo efficacy of human MSC in a rat tissue allotransplant model. Interspecies incompatibilities should be taken into consideration when interpreting preclinical data efficacy data in the context of translation to clinical trial. Stem Cells 2018;36:1210-1215.


Subject(s)
Immunomodulation , Mesenchymal Stem Cells/cytology , Allografts/drug effects , Allografts/physiology , Animals , Cell Proliferation/drug effects , Cytokines/pharmacology , Graft Survival/drug effects , Graft Survival/immunology , Humans , Male , Mesenchymal Stem Cells/drug effects , Phosphorylation/drug effects , Rats, Inbred Lew , Species Specificity
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