Original paperMesenchymal stromal cellsBone marrow-derived mesenchymal stromal cells from patients with end-stage renal disease are suitable for autologous therapy
Introduction
It has been postulated in recent years that mesenchymal stromal cells (MSCs) may be useful in modifying and potentially reversing loss of function in kidney disease and in preventing allograft rejection in transplant recipients 1, 2, 3, 4, 5, 6. MSCs were first discovered in bone marrow (BM) aspirates but have also been isolated and expanded from various other adult tissues (7). At the present time, no unique phenotype has been identified that allows the prospective isolation of MSCs. Their isolation and characterization relies primarily on their ability to adhere to plastic, their multi-lineage differentiation and their membrane antigen profile (8).
Pre-clinical studies indicate that administration of MSCs ameliorates renal injury and accelerates tissue repair, and numerous experimental studies have demonstrated beneficial effects after solid organ transplantation 2, 4, 5, 9, 10, 11, 12, 13. The potential mechanism of MSC-induced kidney repair has been addressed in numerous studies 10, 13, 14, 15, 16, 17, 18. There is increasing evidence that the process of trans-differentiation is rare and of limited biologic relevance (15). It is currently believed that paracrine factors are responsible for the effects of MSCs, including their mitogenic, anti-apoptotic, angiogenic and various immune-modulating properties 19, 20, 21, 22, 23, 24, 25.
In human kidney transplantation, there is great interest in the therapeutic application of MSCs, and the first clinical trials using autologous BM-MSCs in kidney transplantation with the initial focus on their potential as induction therapy and to treat allograft rejection have started 20, 26, 27. A concern for the use of allogeneic MSCs is the potential induction of an allo-response with negative consequences for MSC efficacy and potentially for graft survival in the case of transplantation. A concern for the use of autologous MSCs includes their potential dysfunction secondary to the underlying disease, as reported in systemic lupus erythematosus, immune thrombocytopenic purpura, rheumatoid arthritis, multiple myeloma and aplastic anemia 28, 29, 30, 31, 32, and a potential safety risk related to genetic stability. A few pre-clinical studies have reported on the impact of renal disease on the phenotype and function of MSCs. In mice, functional incompetence of MSCs was reported after exposure to uremic conditions (33). In human BM-MSCs, uremic serum induced an osteoblast-like phenotype accompanied by matrix remodeling and calcification (34), whereas human adipose tissue-derived MSCs are not affected by renal disease (35). None of these studies has studied human BM-MSCs isolated from patients with end-stage renal disease (ESRD); so far, BM-MSCs are the only cell product used in clinical trials with MSCs in nephrology.
We performed a head-to-head comparison between BM-MSCs from patients with ESRD and from healthy controls regarding their phenotypic and functional characteristics. More recently, microRNAs (miRNAs) have been shown to play a critical role in differentiation and MSC functionality (36), and their dysregulation has been shown in various diseases including kidney diseases 37, 38. Because miRNA expression in MSCs from patients with ESRD is completely unknown, we have included in this study comparison of miRNA expression in MSCs from patients with ESRD and healthy controls. We believe our results to be important for clinical application in transplant recipients.
Section snippets
Patients and controls
BM samples were collected from patients with ESRD and from healthy controls that were either BM donors in a clinical renal transplantation setting or patients undergoing orthopedic surgery. Ethics committee approval was obtained for the aspiration protocol, and individual written consents were obtained from all individuals. Two age-matched groups of 10 individuals each were compiled for the analyses.
Isolation and culture of MSCs
Heparinized BM was aspirated under local or general anesthesia. The mononucleated cell fraction
Isolation, expansion and characterization of MSCs
Because differentiation potential and proliferation rate are reported to decline in aged human MSCs 39, 40, we selected two age-matched study populations and used expanded MSC populations at similar low passage numbers (P3–4). Healthy controls (five women and five men) had a median age of 64 years (±7.98), which was comparable to the patients with ESRD. Patient demographics are presented in Table I. The MSC cultures of patients with ESRD and healthy controls showed similar expansion kinetics
Discussion
The great potential for MSCs as a therapeutic tool for allograft rejection after renal transplantation is supported by positive results in different experimental models 5, 9, 11, 13, 41. In these studies, recipient and donor-derived MSCs were shown to have better immunomodulatory properties than third-party MSCs 41, 42, 43, 44. However, donor-derived MSCs were also reported to cause sensitization, and application with autologous MSCs seems preferable 45, 46, 47. The first clinical trials using
Acknowledgments
We thank Ms E. Steeneveld and A. Loor for collecting and archiving donor and patient material and Ms E. van Beelen for the multiplex cytokine analysis. This study was sponsored by the Dutch Organisation for Sciences (NWO/ZonMW; TAS and Veni), a Nephrosearch Grant and the European Community's Seventh Framework Programme (FP7/2007–13, HEALTH-F5-2008-223007 STAR-T REK).
Author contributions are as follows: MEJR, research design, performance of research and data analysis and manuscript preparation;
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