Potential Therapeutic Effects of Long-Term Stem Cell Administration: Impact on the Gene Profile and Kidney Function of PKD/Mhm (Cy/+) Rats

Abstract

Cystic kidney disease (CKD) is a heterogeneous group of genetic disorders and one of the most common causes of end-stage renal disease. Here, we investigate the potential effects of long-term human stem cell treatment on kidney function and the gene expression profile of PKD/Mhm (Cy/+) rats. Human adipose-derived stromal cells (ASC) and human skin-derived ABCB5+ stromal cells (2 × 106) were infused intravenously or intraperitoneally monthly, over 6 months. Additionally, ASC and ABCB5+-derived conditioned media were administrated intraperitoneally. The gene expression profile results showed a significant reprogramming of metabolism-related pathways along with downregulation of the cAMP, NF-kB and apoptosis pathways. During the experimental period, we measured the principal renal parameters as well as renal function using an innovative non-invasive transcutaneous device. All together, these analyses show a moderate amelioration of renal function in the ABCB5+ and ASC-treated groups. Additionally, ABCB5+ and ASC-derived conditioned media treatments lead to milder but still promising improvements. Even though further analyses have to be performed, the preliminary results obtained in this study can lay the foundations for a novel therapeutic approach with the application of cell-based therapy in CKD.

Skin-Derived ABCB5+ Mesenchymal Stem Cells for High-Medical-Need Inflammatory Diseases: From Discovery to Entering Clinical Routine

“…The ABCB5 + MSCs have been studied in polycystic kidney disease (PKD), a group of inherited nephropathies characterized by the formation of multiple fluid-filled cysts in the kidney, which distorts the renal architecture and severely impairs filtration function [129,130]. In the PKD/Mhm (Cy/+) rat model of the most common PKD type, i.e., autosomal dominant PKD (ADPKD) [131], systemic infusions of ABCB5 + MSCs elicited in the kidney cells a reversion of metabolic reprogramming from ADPKD-typical upregulation of alternative pathways of energy production such as glycolysis to oxidative phosphorylation, citrate cycle, gluconeogenesis, and pyruvate metabolism pathways [132]. Besides metabolic reprograming, treatment with ABCB5 + MSCs resulted in downregulation of the PI3K-Akt signaling pathway [132], overactivation of which plays a significant role in PKD cyst formation [133,134], and modulation of several additional pathways involved in apoptosis, cellular senescence, focal adhesion and inflammation [132].…”

“…In the PKD/Mhm (Cy/+) rat model of the most common PKD type, i.e., autosomal dominant PKD (ADPKD) [131], systemic infusions of ABCB5 + MSCs elicited in the kidney cells a reversion of metabolic reprogramming from ADPKD-typical upregulation of alternative pathways of energy production such as glycolysis to oxidative phosphorylation, citrate cycle, gluconeogenesis, and pyruvate metabolism pathways [132]. Besides metabolic reprograming, treatment with ABCB5 + MSCs resulted in downregulation of the PI3K-Akt signaling pathway [132], overactivation of which plays a significant role in PKD cyst formation [133,134], and modulation of several additional pathways involved in apoptosis, cellular senescence, focal adhesion and inflammation [132]. The observed gene profile changes were associated with decreased numbers of renal cysts and apoptotic (TUNEL + ) and proliferative (Ki-67 + ) cells in kidney tissue sections and translated into improvements in renal function as evidenced by enhanced glomerular filtration rate and reduction in proteinuria and albuminuria [132].…”

“…Besides metabolic reprograming, treatment with ABCB5 + MSCs resulted in downregulation of the PI3K-Akt signaling pathway [132], overactivation of which plays a significant role in PKD cyst formation [133,134], and modulation of several additional pathways involved in apoptosis, cellular senescence, focal adhesion and inflammation [132]. The observed gene profile changes were associated with decreased numbers of renal cysts and apoptotic (TUNEL + ) and proliferative (Ki-67 + ) cells in kidney tissue sections and translated into improvements in renal function as evidenced by enhanced glomerular filtration rate and reduction in proteinuria and albuminuria [132]. Therefore, ABCB5 + MSCs might represent a potential candidate therapeutic for reducing cyst growth and improving kidney function in PKD.…”

“…Another potential indication relates to the ability of ABCB5 + MSCs to reverse metabolic reprogramming in polycystic kidney cells [132], which might qualify ABCB5 + MSCs as a potential candidate for improving kidney function in diseased kidney.…”

Clinical-grade human skin-derived ABCB5+ mesenchymal stromal cells exert anti-apoptotic and anti-inflammatory effects in vitro and modulate mRNA expression in a cisplatin-induced kidney injury murine model

“…ABCB5+ MSCs have already demonstrated therapeutic efficacy in clinical trials in chronic skin wounds and in recessive dystrophic epidermolysis bullosa ( 14 , 15 ). Preclinical, ABCB5+ MSCs were able to reverse metabolic reprogramming in polycystic kidney cells ( 16 ). Based on these encouraging results, we decided to investigate the potential efficacy of these cells for treatment of cisplatin-induced kidney injury.…”