Repeated Systemic Administration of Human Adipose-Derived Stem Cells Attenuates Overt Diabetic Nephropathy in Rats

Abstract

Adipose-derived stem cells (ASCs) can alleviate acute kidney injury and promote kidney cell regeneration and repair. To investigate the role of ASCs in diabetic nephropathy (DN), Sprague-Dawley rats were made diabetic by intraperitoneal injection of streptozotocin (STZ) after uninephrectomy. After 12 weeks, proteinuria was well established. Five times of 5 · 10 6 human ASCs repeatedly injected through a tail vein at 4 weekly intervals. A reduction in proteinuria was not observed in diabetic rats until 24 weeks. However, urinary protein excretion was significantly suppressed at 28 weeks and persisted up to 32 weeks after STZ treatment. ASC treatment significantly attenuated glomerulus hypertrophy and tubular interstitial injury, and led to the downregulation of WT-1 and synaptopodin expression. CFSE labeled ASCs were injected into DN rats via the tail vein. Within 24 h after injection, the cells were detected in lung, spleen, and peritubular regions, but rarely in pancreas. Human Alu gene expression was detected in lung and spleen up to 4 weeks after ASCs injection. ASC treatment did not improve hyperglycemia or pancreatic damage. In vitro, recombinant human glial cell line-derived neurotrophic factor (GDNF) prevented podocyte injury by high glucose similarly to ASC-conditioned medium. After blocking GDNF in ASC-CM with neutralizing antibody, the therapeutic effect of ASC-CM was significantly decreased. ASCs cocultured with podocytes restored the downregulation of synaptopodin expression, which was weakened by GDNF-RNA interfering. These findings indicate that repeated intravenous ASC can reduce diabetic kidney damage in rats even at the progressive stage, and promote podocyte recovery via GDNF secretion.

Pulsed Focused Ultrasound Pretreatment Improves Mesenchymal Stromal Cell Efficacy in Preventing and Rescuing Established Acute Kidney Injury in Mice

“…Increased survival, improved renal function, and increased levels of chemoattractants by pFUS during early AKI or clinically established AKI suggest that therapies using pFUS and MSC may be possible during subacute or chronic phases of pathology. pFUS induction of a transient molecular zip‐code might allow multiple courses of cell therapy, a regenerative medicine approach with some promise , that is analogous to metronomic anticancer therapy. Extending the oncological analogy, pFUS can be further characterized as a neoadjuvant approach for infused cell therapies by altering the targeted microenvironment to induce an EHPR effect and improve functional outcomes.…”

Paracrine Proangiogenic Function of Human Bone Marrow-Derived Mesenchymal Stem Cells Is Not Affected by Chronic Kidney Disease

“…Clinical studies have shown that single administrations of allogeneic MSCs are safe and potentially effective in ischemic heart disease [30]. Preclinical studies have shown that in CKD, repeated injections are often required to ameliorate disease progression [31,32], which may increase the likelihood of sensitization which is less desirable in patients likely to require a kidney transplant. Autologous MSCs may thus be preferable for these patients, provided there is limited disease-related dysfunction as we have demonstrated in the present study.…”

Stem cell-derived exosomes: a novel vector for tissue repair and diabetic therapy

“…There is evidence that exosomes may be able to aid in the treatment of diabetic nephropathy. Studies have found that stem cells have a reparative effect on renal tissues in both diabetic nephropathy and other kidney diseases (Zhang et al 2013). As previously discussed, the paracrine signaling effect of exosomes may aid in stem cell-mediated regenerative processes, including the repair of renal tissue.…”