Transplantation of human fetal pancreatic progenitor cells ameliorates renal injury in streptozotocin-induced diabetic nephropathy

Abstract

BackgroundDiabetic nephropathy (DN) is a severe complication of diabetes mellitus (DM). Pancreas or islet transplantation has been reported to prevent the development of DN lesions and ameliorate or reverse existing glomerular lesions in animal models. Shortage of pancreas donor is a severe problem. Islets derived from stem cells may offer a potential solution to this problem.ObjectiveTo evaluate the effect of stem cell-derived islet transplantation on DN in a rat model of streptozotocin-induced DM.MethodsPancreatic progenitor cells were isolated from aborted fetuses of 8 weeks of gestation. And islets were prepared by suspension culture after a differentiation of progenitor cells in medium containing glucagon-like peptide-1 (Glp-1) and nicotinamide. Then islets were transplanted into the liver of diabetic rats via portal vein. Blood glucose, urinary volume, 24 h urinary protein and urinary albumin were measured once biweekly for 16 weeks. Graft survival was evaluated by monitoring human C-peptide level in rat sera and by immunohistochemical staining for human mitochondrial antigen and human C-peptide in liver tissue. The effect of progenitor-derived islets on filtration membrane was examined by electron microscopy and real-time polymerase chain reaction (PCR). Immunohistochemical staining, real-time PCR and western blot were employed for detecting fibronectin, protein kinase C beta (PKCβ), protein kinase A (PKA), inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD).ResultsIslet-like clusters derived from 8th gestational-week human fetal pancreatic progenitors survived in rat liver. And elevated serum level of human C-peptide was detected. Blood glucose, 24 h urinary protein and urinary albumin were lower in progenitor cell group than those in DN or insulin treatment group. Glomerular basement membrane thickness and fibronectin accumulation decreased significantly while podocytes improved morphologically in progenitor cell group. Furthermore, receptor of advanced glycation end products and PKCβ became down-regulated whereas PKA up-regulated by progenitor cell-derived islets. And iNOS rose while SOD declined.ConclusionsDN may be reversed by transplantation of human fetal pancreatic progenitor cell-derived islets. And fetal pancreatic progenitor cells offer potential resources for cell replacement therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1253-1) contains supplementary material, which is available to authorized users.

SIRT3 Facilitates Amniotic Fluid Stem Cells to Repair Diabetic Nephropathy Through Protecting Mitochondrial Homeostasis by Modulation of Mitophagy

“…Although some reports have shown that several drugs slow the progression of DN, it is difficult to repair a damaged kidney. In recent years, many studies have demonstrated that stem cell transplantation is effective and safe for slowing the development of DN via the regeneration of glomerular tissue [4, 16]. However, transplanted stem cells seem to remain in an oxidative environment, and oxidative stress induces apoptosis and cell cycle arrest, which reduce transplantation efficiency [37].…”

“…Unfortunately, the molecular mechanisms underlying DN development are still unclear, and thus, no effective drugs are available to control DN. Recently, stem cell transplantation-based therapy has emerged as a novel therapeutic strategy for DN [4, 5]. This regenerative medicine offers a new method for replenishing damaged cells and promoting the recovery of renal function via differentiation into glomeruli or the activation of paracrine cytokine signaling [6, 7].…”

The receptor for advanced glycation endproducts is a mediator of toxicity by IAPP and other proteotoxic aggregates: Establishing and exploiting common ground for novel amyloidosis therapies

“…AGEs have also been implicated in destabilizing PDX‐1 protein, a critical factor for β‐cell survival, thereby impairing insulin synthesis . Recent breakthroughs in the transplantation of human fetal pancreatic progenitor cells have shown promise in preventing RAGE upregulation in the kidney, protecting against diabetic nephropathy . While these advancements are encouraging, more work is needed to fully determine how RAGE and its ligands influence pancreatic β‐cell fate, and how modulation of ligand production, engagement of the ligand with the RAGE receptor, RAGE receptor, and DIAPH1‐dependent intracellular processes may be harnessed to prevent β‐cell dysfunction, diabetes induction, and subsequent pathological consequences.…”

The privileged position of glp-1 in diabetic nephropathy

“…[8][9][10][11][12] Diabetic kidney disease occurs in patients with T2DM as a consequence of reduced kidney function, triggered by hypertensive nephrosclerosis and unresolved acute renal failure as the main culminating reasons. [13][14][15][16][17][18][19] Diabetic nephropathy is a diagnosis that refers to specific pathologic structural and functional changes seen in kidneys of patients with T2DM. These changes result in a clinical presentation that is characterized by proteinuria, hypertension, and progressive reductions in kidney function.…”