Advances in Food Technology and Nutritional Sciences

Open journal

ISSN 2377-8350

A New Hypothesis: The Immunomodulatory Effects of Mesenchymal Stromal Cell Derived Extracellular Vesicles in Ischemic Kidney Injury Partly through Spleen

Zou Xiangyu and Zhu Yingjian*

Yingjian Zhu, PhD, MD

Department of Urology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai No 100, Haining Road, Shanghai, PR 200080, China. Tel. 86-21-63240090-3161 Fax: 86-21-63240825 E-mail: zhuyingjian_sjtu@126.com

INTRODUCTION

Ischemia/Reperfusion (I/R) injury could cause the intrinsic acute kidney injury (AKI) and lead to the kidney fibrosis in later stage.1Viable renal cells are unable to repair the necrotic tissues due to their limited capability of regeneration, which results in the damage of renal functions. Despite the renal replacement, there is no specific therapy to improve renal function has been found in decades. These facts reveal us to investigate new strategies to treat AKI.

In recent years, the MSCs-based therapy in AKI provides us a new way to protect the renal functions. MSCs from various sources (such as bone marrow, fetal membrane and adipose) in repairing kidney injury were reported,2,3,4 however, the potential immune rejection, adipogenic differentiation and malignant transformation events of MSCs limit our clinical use. EVs contained in the MSC’s condition medium could repair variety injured organs and also could alleviate I/R injury induced AKI.5,6 EVs acquire the cell surface markers when they are released by different cells and could reach the target organs in body when they were injected intravenously. Our previous studies also found human umbilical cord mesenchymal cells derived EVs reached the spleen , lungs and injured kidney in a rat AKI model and it could attenuate the ischemic kidney injury,7 which is consistent with the recent published results.8 MSC-EVs could alleviate kidney injury and protect the renal functions in the different AKI animal models, and both the MSCs and MSC-EVs have the anti-inflammation characters via decreasing the pro-inflammation cells and factors in ischemic injured kidneys.7,9,10,11 The inflammation level of ischemic kidney depends on the regulation of the whole body. As one of the most important immune organs in the body, spleen has the inflammatory cell regulation functions under different stresses and it could directly affect the circulating inflammatory mediators. The inflammatory cells in the spleen have an important role in the physiopathology of ischemic AKI, and it has been demonstrated that MSCs attenuate ischemic AKI trough immunomodulatory effects in a spleen depended manner, which means that MSCs would lose these effects without the spleen.12 However, the possible mechanisms of MSC-EVs in IRI AKI remain unclear.

HYPOTHESIS

The effects of MSC-EVs in ischemic AKI are multiple and the immune systems have vital functions in kidney I/R injury. The immunomodulatory effects of MSC-EVs in ischemic kidney injury partly through spleen. (Figure 1).

NPOJ-1-105 Fig 1

Figure 1: EVs derived from mesenchymal stromal cells have the therapy effects in AKI through accommodating both the systemic immune responses and chemokine in injured kidneys. After admination of MSC-EVs in ischemic kidney models, EVs could reach the targeted organs (spleen and injured kidneys) to change the systemic immune responses (such as change the phenotypes of T cells, NK cells, NKT cells or Tregs) and chemokine levels in injured kidneys (CX3C, ICAM-1, CXC, MCP-1, et al). Through the combined effects above, EVs ultimately lead to regulate inflammatory levels in the ischemic kidney and attenuate kidney injury.

Evaluation of the Hypothesis

The physiopathology of ischemic AKI is complex and the role of inflammation in AKI has been well known.13,14 The alternation of inflammatory cells and factors in different milieus may exert different effects. In the initiation and extension of ischemic AKI, pro-inflammation cells are increased and activated in the injured kidney. Studies have shown that T cells are the key mediators in ischemic AKI and the regulation T cells (Tregs) have the reno-protective effects.15,16 Pro-inflammation cells could directly kill the tubular epithelial cells or secrete proinflammatory factors to lead the kidney damages indirectly.17,18,19,20 Then the inhibitions of some inflammatory pathways were used to attenuate organ I/R injury. Researchers have also found that it could significantly decrease the renal tubular apoptosis and protect the kidney functions in AKI animal models when depleting some inflammatory related cells and pro-inflammatory factors.21,22

Different tissue sources acquired MSCs and MSC-EVs are used to regulate inflammatory response in injured organs. MSCs could exhibit immunosuppressive or immunomodulatory properties by inhibiting T cells and NK cells.23,24 The down-regulation of TNF-a, IL-6, macrophages and up-regulation of the IL10, IL-4, Bfgf were also found after MSCs treatment in injured kidney.25,26,27,28 What is more, in the acute lung injury mice model, MSCs derived EVs reduced the neutrophils and inflammation factors both in injured lungs and plasma, and the macrophage inflammation protein-2 in the injured lungs also changed.29 The infiltration of different inflammatory cells in injured kidneys depends on the cells that transmigration across the vascular endothelium in serum. As one of the most important immune organ in the body, spleen has the inflammatory cell regulation function under different stresses and it could directly affect the circulating mediators or signals. The immune cells in the spleen participate the physiopathology of AKI,30,31 and Jie Hu, et al. also demonstrated that MSCs attenuate AKI by immunomodulatory effects in a spleen depended manner.12 Meanwhile, the transmigration of inflammatory cells across the vascular endothelium into kidneys depends upon various adhesion molecules, chemokine and their receptors.32 Studies have showed that a large number of chemokine like CCL2, CXCL8 are increased in kidney after ischemic AKI.33 Moreover, activated tubular epithelial cells could express Intercellular adhesion molecule-1 (ICAM-1) and P-select in to interact with the neutrophils, monocytes and T cells.34 These factors are generated by the tubular epithelium or vascular endothelial cells in injured kidney to attract inflammatory cells. So both the immune cells in circulation systems and chemokines in injured kidneys determine the ultimate inflammation levels in injured organs.

EVs are small vesicles in the condition medium with an average about 100 nm sizes. So compared to MSCs, EVs could not only recognize the target cells via specific surface receptors, but also could reach various organs in body via circulation systems. After recognition of the target cells, EVs could change target cell phenotypes by delivering bioactive substances, such as proteins, mRNAs and miRNAs.35,36 Researchers have proved that endothelial cell derived EVs are able to reprogram vascular cells by transfer mRNAs and MSC-EVs protect the kidney tubular cells by transfer related miRNAs.37,38,39 Until now, various mRNAs in the MSC-EVs have been found, such as cell cycle related SUMO1, transcription factors related Interferon regulatory factor 6 and it also has the immune regulation related Interleukin 1receptor antagonist and Cytokine receptor-like factor 1.38 What is more, several recent reports have demonstrated that the effect of EVs is limited not only to local kidneys but to other organs,8,40 which may suggest the presence of a systemic effect of EVs in ischemic AKI. Based on the above facts, we hypothesize that MSC-EVs exist immunomodulatory effects in ischemic kidney injury and these effects partly through spleen.

However, there were still some questions for further detail research. First, there are many inflammatory cells in the physiopathology of ischemic AKI, any of these might be involved in EVs’ therapy effects. In the previous studies, macrophages and T cells were involves in the protective role of MSCs in renal IRI.12,41 As for the EVs derived from MSCs, we may focus these cells for the further research. Second, the inflammation related chemokine in ischemic kidneys are multiple, such as CX3C, CXC, MCP-1, et al. To ensure the main cells and (or) factors in this process is the next works. Third, how MSC-EVs change these cell phenotypes or proteins remains controversy. Some studies showed that EVs derived from various sources could horizontal transfer nuclear acids, functional proteins, bioactive membrane and other materials to target cells.42,43 In our opinion any way cannot be excluded. All of these should be explicated in future research.

Consequences of the Hypothesis

Ischemic AKI is a serious condition that occurs in clinical treatment, and MSC-MVs provide the same or better therapeutic effect when compared to MSCs. In the previous studies researchers found that MSCs have the immunomodulatory effects in ischemic kidney injury in a spleen depended manner. As for the immunomodulatory effects of MSC-EVs in organ injury repair still unknown, so we hypothesize here that both systemic inflammatory cells and local kidney chemokines are regulated by MSC-EVs and these effects partly through spleen, which propose a new sight in MSC-EVs’ treatment and supply the theoretical basis for the direction of clinical use.

COMPETING INTERESTS

The authors declare that they have no competing interests.

ACKNOWLEDGEMENTS

This study is supported by grants from the National Natural Science Foundation of China (81170642 and 81470919) and the fund of Shanghai First People’s Hospital (12RC04).

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