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      Mesenchymal Stem Cells in Renal Fibrosis: The Flame of Cytotherapy

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          Abstract

          Renal fibrosis, as the fundamental pathological process of chronic kidney disease (CKD), is a pathologic extension of the normal wound healing process characterized by endothelium injury, myofibroblast activation, macrophage migration, inflammatory signaling stimulation, matrix deposition, and remodelling. Yet, the current method of treating renal fibrosis is fairly limited, including angiotensin-converting enzyme inhibition, angiotensin receptor blockade, optimal blood pressure control, and sodium bicarbonate for metabolic acidosis. MSCs are pluripotent adult stem cells that can differentiate into various types of tissue lineages, such as the cartilage (chondrocytes), bone (osteoblasts), fat (adipocytes), and muscle (myocytes). Because of their many advantages like ubiquitous sources, convenient procurement and collection, low immunogenicity, and low adverse effects, with their special identification markers, mesenchymal stem MSC-based therapy is getting more and more attention. Based on the mechanism of renal fibrosis, MSCs mostly participate throughout the renal fibrotic process. According to the latest and overall literature reviews, we aim to elucidate the antifibrotic mechanisms and effects of diverse sources of MSCs on renal fibrosis, assess their efficacy and safety in preliminarily clinical application, answer the controversial questions, and provide novel ideas into the MSC cellular therapy of renal fibrosis.

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          Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury.

          We report the identification of rat and human cDNAs for a type 1 membrane protein that contains a novel six-cysteine immunoglobulin-like domain and a mucin domain; it is named kidney injury molecule-1 (KIM-1). Structurally, KIM-1 is a member of the immunoglobulin gene superfamily most reminiscent of mucosal addressin cell adhesion molecule 1 (MAdCAM-1). Human KIM-1 exhibits homology to a monkey gene, hepatitis A virus cell receptor 1 (HAVcr-1), which was identified recently as a receptor for the hepatitis A virus. KIM-1 mRNA and protein are expressed at a low level in normal kidney but are increased dramatically in postischemic kidney. In situ hybridization and immunohistochemistry revealed that KIM-1 is expressed in proliferating bromodeoxyuridine-positive and dedifferentiated vimentin-positive epithelial cells in regenerating proximal tubules. Structure and expression data suggest that KIM-1 is an epithelial cell adhesion molecule up-regulated in the cells, which are dedifferentiated and undergoing replication. KIM-1 may play an important role in the restoration of the morphological integrity and function to postischemic kidney.
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            Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro

            Introduction Administration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro. Methods We constructed cisplatin-induced AKI rat models. At 24 h after treatment with cisplatin, hucMSC-ex were injected into the kidneys via the renal capsule; human lung fibroblast (HFL-1)-secreted exosomes (HFL-1-ex) were used as controls. All animals were killed at day 5 after administration of cisplatin. Renal function, histological changes, tubular apoptosis and proliferation, and degree of oxidative stress were evaluated. In vitro, rat renal tubular epithelial (NRK-52E) cells were treated with or without cisplatin and after 6 h treated with or without exosomes. Cells continued to be cultured for 24 h, and were then harvested for western blotting, apoptosis and detection of degree of oxidative stress. Results After administration of cisplatin, there was an increase in blood urea nitrogen (BUN) and creatinine (Cr) levels, apoptosis, necrosis of proximal kidney tubules and formation of abundant tubular protein casts and oxidative stress in rats. Cisplatin-induced AKI rats treated with hucMSC-ex, however, showed a significant reduction in all the above indexes. In vitro, treatment with cisplatin alone in NRK-52E cells resulted in an increase in the number of apoptotic cells, oxidative stress and activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway followed by a rise in the expression of caspase 3, and a decrease in cell multiplication, while those results were reversed in the hucMSCs-ex-treated group. Furthermore, it was observed that hucMSC-ex promoted cell proliferation by activation of the extracellular-signal-regulated kinase (ERK)1/2 pathway. Conclusions The results in the present study indicate that hucMSC-ex can repair cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro. This suggests that hucMSC-ex could be exploited as a potential therapeutic tool in cisplatin-induced nephrotoxicity.
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              Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration.

              Mesenchymal stem cells (MSCs) commonly defined by in vitro functions have entered clinical application despite little definition of their function in residence. Here, we report genetic pulse-chase experiments that define osteoblastic cells as short-lived and nonreplicative, requiring replenishment from bone-marrow-derived, Mx1(+) stromal cells with "MSC" features. These cells respond to tissue stress and migrate to sites of injury, supplying new osteoblasts during fracture healing. Single cell transplantation yielded progeny that both preserve progenitor function and differentiate into osteoblasts, producing new bone. They are capable of local and systemic translocation and serial transplantation. While these cells meet current definitions of MSCs in vitro, they are osteolineage restricted in vivo in growing and adult animals. Therefore, bone-marrow-derived MSCs may be a heterogeneous population with the Mx1(+) population, representing a highly dynamic and stress responsive stem/progenitor cell population of fate-restricted potential that feeds the high cell replacement demands of the adult skeleton. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Stem Cells Int
                Stem Cells Int
                SCI
                Stem Cells International
                Hindawi
                1687-966X
                1687-9678
                2019
                13 January 2019
                : 2019
                : 8387350
                Affiliations
                1Transplantation Center of The 3rd Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
                2Research Center of National Health Ministry on Transplantation Medicine, Changsha, Hunan 410013, China
                3Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
                Author notes

                Guest Editor: Sicai Zhang

                Author information
                http://orcid.org/0000-0001-5225-9282
                http://orcid.org/0000-0002-2334-6624
                http://orcid.org/0000-0003-4728-9393
                http://orcid.org/0000-0003-4028-2682
                http://orcid.org/0000-0002-9743-9882
                http://orcid.org/0000-0002-3004-4405
                Article
                10.1155/2019/8387350
                6350586
                30766607
                47259eab-4ba4-43ba-be05-ae8f0734b30e
                Copyright © 2019 Quan Zhuang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 September 2018
                : 27 November 2018
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81700658
                Award ID: 81771722
                Funded by: Natural Science Foundation of Hunan Province
                Award ID: 2016JJ4105
                Funded by: Central South University
                Award ID: JY201629
                Award ID: ZY20180983
                Award ID: ZY20180988
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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