Transplantation of adipose‐derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model

Abstract

Aims/Introduction: Adipose-derived mesenchymal stem cell (ASC) transplantation is a promising therapy for diabetic nephropathy (DN). However, intravascular administration of ASCs is associated with low engraftment in target organs. Therefore, we considered applying the cell sheet technology to ASCs. In this study, ASC sheets were directly transplanted into the kidneys of a DN rat model, and therapeutic consequences were analyzed. Materials and Methods: Adipose-derived mesenchymal stem cells were isolated from adipose tissues of 7-week-old enhanced green fluorescent protein rats, and ASC sheets were prepared using a temperature-responsive culture dish. A DN rat model was established from 5-week-old Spontaneously Diabetic Torii fatty rats. Seven-week-old DN rats (n = 21) were assigned to one of the following groups: sham-operated (n = 6); ASC suspension (6.0 9 10 6 cells/mL) administered intravenously (n = 7); six ASC sheets transplanted directly into the kidney (n = 8). The therapeutic effect of the cell sheets was determined based on urinary biomarker expression and histological analyses. Results: The ASC sheets survived under the kidney capsule of the DN rat model for 14 days after transplantation. Furthermore, albuminuria and urinary tumor necrosis factor-a levels were significantly lower in the ASC sheets transplanted directly into the kidney group than in the sham-operated and ASC suspension administered intravenously groups (P < 0.05). Histologically, the ASC sheets transplanted directly into the kidney group presented mild atrophy of the proximal tubule and maintained the renal tubular structure. Conclusions: Transplantation of ASC sheets directly into the kidney improved transplantation efficiency and suppressed renal injury progression. Therefore, the ASC sheet technology might be a promising novel treatment for DN.Although strict glycemic control is reported to suppress the progression of DN 6,7 , there is no treatment to stop DN progression. Recently, mesenchymal stem cell (MSC) transplantation has received substantial attention as a therapy for DN. MSCs can differentiate into adipogenic and osteogenic cells 8 , and possess clinically useful properties, such as low antigenicity 9,10 and paracrine effects through cytokines 11,12 . In particular, adipose-derived mesenchymal stem cells (ASCs) represent an attractive cell source owing to their abundance in the body 13,14 .In animal experiments on DN, intravascular administration of ASC suspensions was shown to suppress the progression of

The future of diabetic kidney disease management: what to expect from the experimental studies?

“…Repeated intravenous injections of ad-MSCs attenuated glomerulus hypertrophy and urinary protein excretion in STZ-induced diabetic rats [58]. Moreover, Takemura et al showed that transplantation of ad-MSCs under the renal capsule of Spontaneously Diabetic Torii fatty rats attenuates glomerular and tubular injury to a greater extend compared to ad-MSCs administrated per intravenous route [59]. Finally, Lee SE et al have shown that treatment with ad-MSCs prevented albuminuria and tubular epithelial cell injury via induction of the Arginase-1, a marker of M2 macrophages, and subsequent improvement of mitochondrial function [60] Although these pre-clinical studies in DKD suggest that MSC-based therapy may represent a novel promising tool for DKD treatment, the experimental design of these studies is heterogeneous in terms of cell types, doses, administration route, diabetes duration, making it difficult to translate these findings into clinical practice.…”

Mesenchymal Stem Cells Transplantation in Diabetic Kidney Diseases: A Systematic Review and Meta-analysis

“…Glucose was almost detected after the MSCs treatment, except for 2 studies [27,32]. Sixteen studies measured glucose for once at the end of the experiment [13-16, 18-24, 26, 28-31].…”

“…Multiple intravenous infusion of ADSCs could attenuate in ammation, promote tissue repair and improve the prognosis of the long-term complications of T2DM [33]. Compared with intravenous injection, ADSCs sheet transplantation to the kidney had the advantage of higher e ciency [32]. Because of the importance of microvesicle, ultrasonic technology has been studied for microvesicles destruction to make them take effect easily.…”

Administration of Mesenchymal Stem Cells in Diabetic Kidney Disease: A Systematic Review and Meta-analysis

“…Glucose was detected after MSC treatment in all but 2 studies [32,37]. Sixteen studies measured glucose once at the end of the experiment [18-21, 23-29, 31, 33-36].…”