Mesenchymal stromal cellsAutologous transplantation of mesenchymal stromal cells tends to prevent progress of interstitial fibrosis in a rhesus Macaca mulatta monkey model of chronic kidney disease
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.
References (44)
- et al.
Nephrotoxicity induced by cancer chemotherapy with special emphasis on cisplatin toxicity
Am J Kidney Dis
(1986) - et al.
Cisplatin nephrotoxicity: mechanisms and renoprotective strategies
Kidney Int
(2008) - et al.
Multipotent mesenchymal stem cells reduce interstitial fibrosis but do not delay progression of chronic kidney disease in collagen4A3-deficient mice
Kidney Int
(2006) - et al.
Mesenchymal stem cells ameliorate experimental peritoneal fibrosis by suppressing inflammation and inhibiting TGF-beta1 signaling
Kidney Int
(2013) - et al.
Intra-renal arterial injection of autologous bone marrow mesenchymal stromal cells ameliorates cisplatin-induced acute kidney injury in a rhesus Macaque mulatta monkey model
Cytotherapy
(2014) - et al.
Nephrotoxicity from chemotherapeutic agents: clinical manifestations, pathobiology, and prevention/therapy
Semin Nephrol
(2010) - et al.
Cisplatin nephrotoxicity may be sex related
Kidney Int
(2013) - et al.
Severely damaged kidneys possess multipotent renoprotective stem cells
Cytotherapy
(2010) - et al.
The effect of antioxidant on development of fibrosis by cisplatin in rats
J Pharmacol Sci
(2009) - et al.
Effect of whole bone marrow cell infusion in the progression of experimental chronic renal failure
Transplant Proc
(2008)
Transplantation of bone marrow-derived MSCs improves cisplatinum-induced renal injury through paracrine mechanisms
Exp Mol Pathol
Mesenchymal stem cells infusion prevents acute cellular rejection in rat kidney transplantation
Transplant Proc
An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity
Crit Rev Toxicol
The role of mesenchymal stem cells in the functional improvement of chronic renal failure
Stem Cells Dev
Concise review: stem/progenitor cells for renal tissue repair: current knowledge and perspectives
Stem Cells Transl Med
Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy
World J Stem Cells
Therapeutic effects of human amniotic fluid-derived stem cells on renal interstitial fibrosis in a murine model of unilateral ureteral obstruction
PLoS One
Human Wharton's jelly-derived mesenchymal stromal cells reduce renal fibrosis through induction of native and foreign hepatocyte growth factor synthesis in injured tubular epithelial cells
Stem Cell Res Ther
Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury
Exp Biol Med (Maywood)
Amniotic fluid-derived mesenchymal stem cells prevent fibrosis and preserve renal function in a preclinical porcine model of kidney transplantation
Stem Cells Transl Med
Safety and efficacy of intravenous infusion of allogeneic cryopreserved mesenchymal stem cells for treatment of chronic kidney disease in cats: results of three sequential pilot studies
Stem Cell Res Ther
Differential gender differences in ischemic and nephrotoxic acute renal failure
Am J Nephrol
Cited by (18)
Hypoxia Enhanced Bone Regeneration Through the HIF-1α/β-Catenin Pathway in Femoral Head Osteonecrosis
2021, American Journal of the Medical SciencesCitation Excerpt :Furthermore, the present study indicated that using BMSCs treated with normoxia also provided better outcomes in bone repair than the control group. However, it is difficult for BMSCs to maintain normal proliferation and osteogenic differentiation in the face of ischemia, hypoxia, and nutrient deficiency in the necrotic region of the femoral head, which results in BMSC apoptosis within 48 h of transplantation.23,27 Consequently, it may impede the use of BMSCs in clinical settings.
Bone marrow–mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up
2018, CytotherapyCitation Excerpt :Previously we reported that gentamicin nephrotoxicity could be ameliorated by human MSC–conditioned medium (MSC-CM) [21]. Furthermore, we stated that intrarenal arterial infusion of BM-MSCs improved renal function and structure in an acute kidney injury (AKI) model [22] and a CKD model of rhesus Macaca mulatta monkey [23]. Moreover, an Egyptian group showed that infusion of MSCs in patients with CKD was promising; however, they did not report and discuss any safety issues [24,25].
Therapeutic application of extracellular vesicles in acute and chronic renal injury
2017, NefrologiaCitation Excerpt :Administration of MSCs from adipose tissue after a percutaneous transluminal renal angioplasty improves renal function.81 In the model of cisplatin induced chronic kidney disease in non-human primates, the preventive use of autologous BM-MSCs delayed the progression of interstitial fibrosis, but it could not reverse established damage.82 In clinical studies the administration of 3 doses of allogeneic BM-MSCs to a patient with recurrent focal and segmental glomerulosclerosis after kidney transplantation reduced the proteinuria and helped to maintain stable renal function and avoid conventional treatment with weekly plasmapheresis.83
Bone marrow mesenchymal stromal cells ameliorate angiogenesis and renal damage via promoting PI3k-Akt signaling pathway activation in vivo
2016, CytotherapyCitation Excerpt :The present experimental and clinical studies showed that MSC therapy has become a promising approach for treatment of tissue ischemia associated with myocardial infarction, ischemic stroke and peripheral arterial disease [15–18], which have shown encouraging results. Furthermore, the positive therapeutic action of MSCs in different CKD animal models have been reported recently [19,20], in part by improvement in renal function [21,22], renal fibrosis [23,24] and glomerulosclerosis [25]. Consistent with previous studies on the effects of BM-MSCs on CKD, this study showed that the transplantation of BM-MSCs improved renal dysfunction.
The therapeutic potential of Camel Wharton jelly mesenchymal stem cells (CWJ-MSCs) in canine chronic kidney disease model
2022, Stem Cell Research and Therapy