Mesenchymal stromal cells reset the scatter factor system and cytokine network in experimental kidney transplantation

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Abstract

Background

In former studies we showed in a rat model of renal transplantation that Mesenchymal Stromal Cells (MSC) prevent acute rejection in an independent way of their endowing in the graft. In this study we investigated whether MSC operate by resetting cytokine network and Scatter Factor systems, i.e. Hepatocyte Growth Factor (HGF), Macrophage Stimulating Protein (MSP) and their receptors Met and RON, respectively.

Methods

MSC were injected into the renal artery soon after reperfusion. Controls were grafted untreated and normal rats. Rats were sacrificed 7 days after grafting. Serum and renal tissue levels of IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10, MSP/RON, HGF/Met systems, Treg lymphocytes were investigated.

Results

In grafted untreated rats IFN-γ increased in serum and renal tissue and IL-6 rose in serum. MSC prevented both the phenomena, increased IL-10 serum levels and Treg number in the graft. Furthermore MSC increased serum and tissue HGF levels, Met tubular expression and prevented the suppression of tubular MSP/RON expression.

Conclusions

Our results demonstrate that MSC modify cytokine network to a tolerogenic setting, they suppress Th1 cells, inactivate monocytes/macrophage, recruit Tregs. In addition, MSC sustain the expression of the Scatter Factor systems expression, i.e. systems that are committed to defend survival and stimulate regeneration of tubular cells.

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Most cited references 51

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Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

Florian Tögel, Zhuma Hu, Kathleen A. Weiss … (2005)

Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.

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Mechanisms of mesenchymal stromal cell immunomodulation.

Karen English (2013)

Multipotent mesenchymal stromal cells (MSCs) have generated considerable interest in the fields of regenerative medicine, cell therapy and immune modulation. Over the past 5 years, the initial observations that MSCs could enhance regeneration and modulate immune responses have been significantly advanced and we now have a clearer picture of the effects that MSCs have on the immune system particularly in the context of inflammatory-mediated disorders. A number of mechanisms of action have been reported in MSC immunomodulation, which encompass the secretion of soluble factors, induction of anergy, apoptosis, regulatory T cells and tolerogenic dendritic cells. It is clear that MSCs modulate both innate and adaptive responses and evidence is now emerging that the local microenvironment is key in the activation or licensing of MSCs to become immunosuppressive. More recently, studies have suggested that MSCs have the capacity to sense their environment and have a role in pathogen clearance in conjunction with the resolution of insult or injury. This review focuses on the mechanisms of MSC immunomodulation discussing the multistep process of MSC localisation at sites of inflammation, the cross talk between MSCs and the local microenvironment as well as the subsequent mechanisms of action used to resolve inflammation.

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Immunomodulation by mesenchymal stem cells and clinical experience.

K Le Blanc, O Ringdén (2007)

Mesenchymal stem cells (MSCs) from adult marrow can differentiate in vitro and in vivo into various cell types, such as bone, fat and cartilage. MSCs preferentially home to damaged tissue and may have therapeutic potential. In vitro data suggest that MSCs have low inherent immunogenicity as they induce little, if any, proliferation of allogeneic lymphocytes. Instead, MSCs appear to be immunosuppressive in vitro. They inhibit T-cell proliferation to alloantigens and mitogens and prevent the development of cytotoxic T-cells. In vivo, MSCs prolong skin allograft survival and have several immunomodulatory effects, which are presented and discussed in the present study. Possible clinical applications include therapy-resistant severe acute graft-versus-host disease, tissue repair, treatment of rejection of organ allografts and autoimmune disorders.

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Author and article information

Contributors

Marilena Gregorini: mgregorini@hotmail.com

Francesca Bosio: bosiofrancesca@gmail.com

Chiara Rocca: chiarettaleo@hotmail.it

Valeria Corradetti: valeria.corradetti@gmail.com

Teresa Valsania: t.valsania@hotmail.com

Eleonora Francesca Pattonieri: ef.pattonieri@gmail.com

Pasquale Esposito: pasqualeesposito@hotmail.com

Giulia Bedino: giuliabedino@yahoo.it

Chiara Collesi: chiara.collesi@icgeb.org

Carmelo Libetta: carmelo.libetta@unipv.it

Francesco Frassoni: francescofrassoni@hsanmartino.it

Antonio Dal Canton: dalcanton@smatteo.pv.it

Teresa Rampino: t.rampino@smatteo.pv.it

Journal

Journal ID (nlm-ta): BMC Immunol

Journal ID (iso-abbrev): BMC Immunol

Title: BMC Immunology

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2172

Publication date (Electronic): 3 October 2014

Publication date PMC-release: 3 October 2014

Publication date Collection: 2014

Volume: 15

Issue: 1

Electronic Location Identifier: 44

Affiliations

[ ]Unit of Nephrology, Dialysis and Transplantation, Fondazione, IRCCS Policlinico San Matteo and University of Pavia, viale Golgi 19, 27100 Pavia, Italy

[ ]Unit of Nephrology, Dialysis and Transplantation, Fondazione, IRCCS Policlinico San Matteo, viale Golgi 19, 27100 Pavia, Italy

[ ]ICGEB, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

[ ]Stem Cells Therapy and Hemato-Oncology, S.Martino Hospital, 16100 Genoa, Italy

Article

Publisher ID: 44

DOI: 10.1186/s12865-014-0044-1

PMC ID: 4193986

PubMed ID: 25277788

SO-VID: 91119c0c-e6db-4b3c-ba53-93950cd8430b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 7 February 2014

Date accepted : 25 September 2014

Custom metadata

ScienceOpen disciplines: Immunology

Keywords: mesenchymal stromal cells,acute kidney rejection,experimental model,hepatocyte growth factor,macrophage stimulating protein,scatter factors

Data availability:

ScienceOpen disciplines: Immunology

Keywords: mesenchymal stromal cells, acute kidney rejection, experimental model, hepatocyte growth factor, macrophage stimulating protein, scatter factors

Mesenchymal stromal cells reset the scatter factor system and cytokine network in experimental kidney transplantation

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Abstract

Background

Methods

Results

Conclusions

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Gamma Delta T cells

Most cited references 51

Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

Mechanisms of mesenchymal stromal cell immunomodulation.

Immunomodulation by mesenchymal stem cells and clinical experience.

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