Therapeutic potential of conditioned medium obtained from deferoxamine preconditioned umbilical cord mesenchymal stem cells on diabetic nephropathy model

Abstract

Background The therapeutic potential of mesenchymal stem cells (MSCs)-derived conditioned media (CM) can be increased after preconditioning with various chemical agents. The aim of this study is comparative evaluation of effects of N-CM and DFS-CM which are collected from normal (N) and deferoxamine (DFS) preconditioned umbilical cord-derived MSCs on rat diabetic nephropathy (DN) model. Methods After incubation of the MSCs in serum-free medium with/without 150 µM DFS for 48 h, the contents of N-CM and DFS-CM were analyzed by enzyme-linked immunosorbent assay. Diabetes (D) was induced by single dose of 55 mg/kg streptozotocin. Therapeutic effects of CMs were evaluated by biochemical, physical, histopathological and immunohistochemical analysis. Results The concentrations of vascular endothelial growth factor alpha, nerve growth factor and glial-derived neurotrophic factor in DFS-CM increased, while one of brain-derived neurotrophic factor decreased in comparison with N-CM. The creatinine clearance rate increased significantly in both treatment groups, while the improvement in albumin/creatinine ratio and renal mass index values were only significant for D + DFS-CM group. Light and electron microscopic deteriorations and loss of podocytes-specific nephrin and Wilms tumor-1 (WT-1) expressions were significantly restored in both treatment groups. Tubular beclin-1 expression was significantly increased for DN group, but it decreased in both treatment groups. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cell death increased in the tubules of D group, while it was only significantly decreased for D + DFS-CM group. Conclusions DFS-CM can be more effective in the treatment of DN by reducing podocyte damage and tubular apoptotic cell death and regulating autophagic activity with its more concentrated secretome content than N-CM. Graphical Abstract

2D and 3D cultured human umbilical cord-derived mesenchymal stem cell-conditioned medium has a dual effect in type 1 diabetes model in rats: immunomodulation and beta-cell regeneration

“…Finally, we demonstrated the isolated cells’ adipogenic and osteogenic differentiation abilities. Thus, by choosing two of the three primary tissues of mesoderm origin, we showed that our cells have MSC characteristics, in line with the studies in the literature [ 29 , 33 – 35 ].…”

Therapeutic Potential of Mesenchymal Stem Cell‐Derived Conditioned Medium for Diabetes Mellitus and Related Complications

“…[41,47,59] MSCs also secrete growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), stromal cell-derived factor-1 (SDF-1), insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), fibroblast growth factor (FGF), [60][61][62][63] neural growth factor (NGF), glial cell-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF). [64] Growth factors are essential effectors, providing therapeutic benefits like tissue repair, protection, fibrogenesis suppression, [65] and angiogenesis induction. [66] Furthermore, they have regulatory impacts on MSCs.…”

“…[116] When the microvascular nature of the DN is considered, the glomeruli and tubular areas are expected to be primarily affected due to the presence of glomerular and peritubular capillaries, respectively. [117] In the glomerulus, the integrity of the glomerular filtration barrier (GFB), which is composed of podocytes along with fenestrated endothelium of capillaries and its basal lamina, is compromised under diabetic conditions, which in turn leads to a slow decline in renal function. [118] Currently, available treatments, including the application of anti-hypertensive drugs and sodium-glucose co-transporter 2 protein inhibitors, slow the progression of the disease.…”

“…However, they are not able to prevent the development of ESKD, which is the situation necessitating the development of novel therapies capable of stopping disease progression. [ 117 ] In this respect, the application of CM obtained from MSCs have promising results in in vitro and in vivo experiments. It was shown that human AT‐MSC‐CM reduced high glucose‐induced apoptosis of podocytes and maintained expressions and arrangements of podocyte‐specific synaptopodin and nephrin proteins via increased concentration of EGF.…”

“…[ 54 ] Moreover, this improvement was found to be associated with more concentrated content of DFX‐CM, specifically NGF and GDNF neuroprotective growth factors and pro‐angiogenic factor VEGF all of which are crucial for the structural and functional integrity of podocytes and capillary endothelium. [ 117 ] This study is also important from another point of view that suitable preconditioning strategies which improve secretome content in favor of therapeutically effective paracrine factor could provide better recuperative results.…”