Enhancing Kidney Vasculature in Tissue Engineering—Current Trends and Approaches: A Review

Chronic kidney diseases are a leading cause of fatalities around the world. As the most sought-after organ for transplantation, the kidney is of immense importance in the field of tissue engineering. The primary obstacle to the development of clinically relevant tissue engineered kidneys is precise vascularization due to the organ’s large size and complexity. Current attempts at whole-kidney tissue engineering include the repopulation of decellularized kidney extracellular matrices or vascular corrosion casts, but these approaches do not eliminate the need for a donor organ. Stem cell-based approaches, such as kidney organoids vascularized in microphysiological systems, aim to construct a kidney without the need for organ donation. These organ-on-a-chip models show complex, functioning kidney structures, albeit at a small scale. Novel methodologies for developing engineered scaffolds will allow for improved differentiation of kidney stem cells and organoids into larger kidney grafts with clinical applications. While currently, kidney tissue engineering remains mostly limited to individual renal structures or small organoids, further developments in vascularization techniques, with technologies such as organoids in microfluidic systems, could potentially open doors for a large-scale growth of whole engineered kidneys for transplantation.

Abstract 471: Combination of Allogeneic Mesenchymal and Kidney Stem Cells Ameliorates Chronic Kidney Disease Induced Heart Failure With Preserved Ejection Fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition involving multiple comorbidities. Phenotypic classification of HFpEF associated with chronic kidney disease (CKD) manifests worse outcomes, compared to other HFpEF phenotypes. Few treatments improve morbidity and mortality in HFpEF. Stem cell therapy promotes cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that allogeneic stem cell treatment ameliorates HFpEF in a large animal model of CKD. Methods: Yorkshire pigs (n=26) underwent 5/6 embolization-mediated nephrectomy and 4-weeks later received either: allogeneic mesenchymal stem cells (MSCs) (10х10 6 ), Kidney stem cells (KSC; 10х10 6 ), combination (ACCT; MSC+KSC; 1:1 ratio [5х10 6 each]), or placebo (n=6-7/ group). Cell therapy was delivered via the patent renal artery of the remnant kidney. RNAsec analysis compared placebo and ACCT groups. Results: Mean arterial pressure increased significantly in the placebo- (21.89±6.05 mmHg, p<0.0001) compared to the ACCT-group (p=0.04) at 12 weeks. Glomerular filtration rate improved significantly in the ACCT group (p=0.002). RNAseq analysis revealed a significant decrease in genes normally increased during kidney transplant rejection (q<10 -6 , NES = -2.32) in ACCT. Consistent with these results, there was a downregulation of canonical drivers of tubular damage and regeneration, including SOX9 (-2.39 fold, p=0.0004) and apoptosis of kidney cell types (-24.89 fold, p=0.004), including podocytes (-2.065 fold, p=0.04) with ACCT. ACCT administration also downregulated genes related to oxidative stress (-4.6 fold, p<0.0001), fibrosis, inflammatory response (-4.760 fold, p=<0.05), and renin-angiotensin signaling (-3.162 fold, p=0.024), which are related to cardiac hypertrophy pathways (-7.23, fold, p<0.0001). EDPVR improved in with ACCT (p=0.003), indicating decreased ventricular stiffness. Ejection fraction, relative wall thickness, and left ventricular mass did not differ between groups at 12 weeks. Conclusion: Intra-renal artery allogeneic cell therapy was safe. Beneficial effects were observed in the ACCT and MSC groups in the kidney and heart. These findings have important implications on the use of cell therapy for HFpEF and cardiorenal syndrome.

Potential role of P2X7 receptor in regulating kidney stem cells in the course of acute kidney injury

<p class="Abstract">The role of the P2X7R in developing acute kidney injury is unknown. In this study, we developed acute kidney injury mouse model system using 0.75% adenine and examined for renal damage using histology on day 2 and day 4. P2X7 antagonist (A438079) was used to study the recovery process after initial damage and it shows positive histological data. The P2X7R expression on the day 2 and day 4 of acute kidney injury was studied using immunohisto-chemistry and Western blotting. Result shows elevated expression as acute kidney injury progress. Later the P2X7R expression was compared with apoptotic signal and stem cell specific marker (CD133). The results conclude that the apoptotic signals are mainly associated with advanced stage of acute kidney injury but not much in day 2. Similarly, CD133 expression was mask-ed in latter stages of injury following elevated expression in the initial stages.</p><p> </p>

Kidney stem cells

End-stage renal failure is a major cause of death with currently only dialysis and transplantation available as therapeutic options, each with its own limitations and drawbacks. To allow regenerative medicine-based kidney replacement therapies and due to the fact that neither haematopoietic stem cells nor mesenchymal stem cells, the most accessible human stem cells, can be used to derive genuine nephron progenitors, much attention has been given to finding adult renal stem cells. Several candidates for this have been described, but their true identity as stem or progenitor cells and their potential use in therapy has not yet been shown. However, the analysis of embryonic renal stem cells, specifically stem/progenitor cells that are induced into the nephrogenic pathway to form nephrons until the 34th week of gestation, has been much more conclusive.