Elsevier

Cytotherapy

Volume 17, Issue 11, November 2015, Pages 1495-1505
Cytotherapy

Mesenchymal stromal cells
Autologous transplantation of mesenchymal stromal cells tends to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease

https://doi.org/10.1016/j.jcyt.2015.06.006Get rights and content

Abstract

Background aims

Chronic kidney disease (CKD) attributed to cisplatin is well documented. Mesenchymal stromal cells (MSCs) are proven to be renotropic. Although they have been shown to improve function in CKD and reduce fibrosis in different experimental rodent models, their efficiency in primates is unknown. The present study aimed to evaluate the prevention of CKD and reduction of fibrosis in monkeys treated with MSCs after cisplatin nephrotoxicity.

Methods

We induced CKD in adult rhesus Macaca mulatta monkeys by means of intravenous administration of cisplatin. Autologous MSCs were transplanted by means of intrarenal arterial injections to assess the adverse effects of cisplatin in two CKD models: preventative and stable. Preventative CKD monkeys (n = 3) underwent cell transplantation 4 days after the cisplatin injection. The stable CKD monkeys (n = 2) underwent cell transplantation 6 months after the cisplatin injection. Non-treated (n = 4) and normal saline–injected animals (n = 3) comprised the control and vehicle groups, respectively. We followed the animals for survival rate, serum biochemistry, urine analysis and histopathological indices.

Results

In the preventive CKD model, MSC transplantation tended to improve some renal functions but significantly reduced the histopathologic score compared with the vehicle and control groups. In the stable CKD model, MSCs did not ameliorate renal function or pathological score.

Conclusions

These results suggest that MSCs tend to delay progression of CKD and fibrosis but do not reduce established interstitial fibrosis in this unique primate model of cisplatin-induced nephrotoxicity.

Introduction

Renal interstitial fibrosis is a common pathological feature after chronic kidney disease (CKD) that frequently leads to end-stage renal disease. Renal interstitial fibrosis occurs in humans 5 months after cisplatin chemotherapy, as evidenced by an altered nephron structure and progressively impaired nephron function, which leads to irreversible renal damage [1]. In clinical practice, approximately one-third of patients have renal dysfunction after treatment with cisplatin [2].

Currently, most renal-protective approaches for fibrosis are only partially beneficial, and patients either remain on dialysis or become candidates for transplantation [3]. Recently, new therapeutic strategies for tissue repair have emerged. One of the most encouraging is the use of stem cell–based therapy, which provides promising results after a toxic/ischemic event or the prevention of CKD [4], [5], [6], [7].

Recently, we showed that intra-renal arterial injection of autologous bone marrow mesenchymal stromal cells (MSCs) ameliorated cisplatin-induced acute kidney injury (AKI) in a rhesus Macaca mulatta monkey model during a short-term 3-month follow-up. In this study, we did not follow the long-term adverse effects of cisplatin after cell transplantation to assess fibrosis progression [8].

MSCs display immunomodulatory and antifibrotic activities that can be important in the response to injury [9]. The antifibrotic effects of cultured MSCs have been demonstrated in different animal models [10], [11], [12], [13], [14]. However, the effects of MSCs in models of chronic and renal fibrosis are controversial [7].

We followed two models of cisplatin-induced nephrotoxic injury (preventive and stable CKD) in the adult rhesus M mulatta monkey over an extended period of time. Our results demonstrated that autologous transplantation of MSCs prevented progression of interstitial fibrosis but did not reduce established fibrosis in the stable CKD model.

Section snippets

CKD monkey model

In this study, we used 15 healthy male rhesus M mulatta monkeys that were 1.5 to 2.5 years old. Monkeys were obtained from the Primate Research Center at Royan Institute. All animal care, experimental and surgical processes and postoperative euthanasia were performed in strict accordance with the ethical principles of the NIH Guide for the Care and Use of Laboratory Animals, after approval by the Institutional Review Board and Institutional Ethical Committee at Royan Institute (No. EC.91.1145).

Characterization of MSCs derived from the stable CKD monkey model

Phase-contrast microscopy of the MSCs culture derived from the cisplatin-induced stable CKD monkey model showed a slightly heterogeneous population composed predominately of long, spindle-shaped cells and a few smaller cells (Figure 1A). The MSCs could differentiate into adipocytes, osteocytes and chondrocytes as shown by oil red O, alizarin red and toluidine blue staining, respectively (Figure 1B–D). The F-CFU assay was used to determine the ability of MSCs to form colonies. MSCs were stained

Discussion

We evaluated the hypothesis that treatment with MSCs could improve renal function and attenuate injury in a rhesus M mulatta monkey CKD model. Previously, we have shown that multipotent MSCs improved the outcome of an AKI model [8]. Whether MSCs can delay renal failure in CKD is not well known.

Initially, we have generated a preventive cisplatin-induced CKD model. Cisplatin-induced nephrotoxicity may range from mild, reversible structural alterations in tubular epithelial cells that induce a

Acknowledgments

This work was supported by a grant from the Royan Charity Association for Health and Royan Institute.

Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.

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