Endovenous Administration of Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells Prevents Renal Failure in Diabetic Mice

Abstract

Twenty-five to 40% of diabetic patients develop diabetic nephropathy, a clinical syndrome that comprises renal failure and increased risk of cardiovascular disease. It represents the major cause of chronic kidney disease and is associated with premature morbimortality of diabetic patients. Multipotent mesenchymal stromal cells (MSC) contribute to the regeneration of several organs, including acutely injured kidney. We sought to evaluate if MSC protect kidney function and structure when endovenously administered to mice with severe diabetes. A month after nonimmunologic diabetes induction by streptozotocin injection, C57BL/6 mice presented hyperglycemia, glycosuria, hypoinsulinemia, massive beta-pancreatic islet destruction, low albuminuria, but not renal histopathologic changes (DM mice). At this stage, one group of animals received the vehicle (untreated) and other group received 2 doses of 0.5 x 10(6) MSC/each (MSC-treated). Untreated DM mice gradually increased urinary albumin excretion and 4 months after diabetes onset, they reached values 15 times higher than normal animals. In contrast, MSC-treated DM mice maintained basal levels of albuminuria. Untreated DM mice had marked glomerular and tubular histopathologic changes (sclerosis, mesangial expansion, tubular dilatation, proteins cylinders, podocytes lost). However, MSC-treated mice showed only slight tubular dilatation. Observed renoprotection was not associated with an improvement in endocrine pancreas function in this animal model, because MSC-treated DM mice remained hyperglycemic and hypoinsulinemic, and maintained few remnant beta-pancreatic islets throughout the study period. To study MSC biodistribution, cells were isolated from isogenic mice that constitutively express GFP (MSC(GFP)) and endovenously administered to DM mice. Although at very low levels, donor cells were found in kidney of DM mice 3 month after transplantation. Presented preclinical results support MSC administration as a cell therapy strategy to prevent chronic renal diseases secondary to diabetes.

The Role of Stem Cell Injection in Amelioration of Diabetic Nephropathy in Experimentally Induced Diabetic Rats.

“…In contrast to these results, Ezquer et al [30]administered syngeneic MSCs in a mouse model that develops severe diabetes. Despite not sharing the etiology of either T1DM or T2DM, these animals showed a rapid progression of renal failure and developed most of the pathognomonic signs of DN.…”

MSC transplantation: a promising therapeutic strategy to manage the onset and progression of diabetic nephropathy

“…due to hyperglycemia correction, or direct, i.e. due to protection/regeneration of renal tissue, we administered syngeneic MSCs in a mouse model that develops severe diabetes after the in fusion of a single high dose of streptozotocin (Ezquer et al, 2009). Despite not sharing the etiology of either T1DM or T2DM, these animals showed a rapid progression of renal failure and developed most of the pathognomonic signs of DN.…”

Mesenchymal stem cells for the treatment of tendon disorders

“…In order to transfer experimental data to the clinic, relevant tracking models for the cells should be constructed, such models include labelling the cells (immunolabeling, membrane soluble dyes, gene transfer) or utilizing non-autologous cells, such as human cells transplanted into an animal or allogeneic cells from an animal of the opposite sex and staining for the Y chromosome. An example of a MSC biodistribution study was published by Ezquer [77], in which the authors found systemically implanted MSCs in the bone marrow, kidneys and heart. Data on the migration and biodistribution of autologous MSCs in humans have not yet been published; however, the distribution of a similar cell type, bone marrow mononuclear cells (BMMCs), was analysed after intravenous injection [78].…”