Principal Scientist Trestle Biotherapeutics San Diego, California, United States
Abstract: Chronic kidney disease is a global health crisis, with end-stage renal disease (ESRD) patients requiring long-term dialysis or kidney transplantation. Dialysis has an exceptionally low 5-year survival of under 40%, restores only partial renal function, and is associated with both high healthcare costs and low quality of life for patients. Kidney transplantation remains the only cure for ESRD, but is severely hindered by the organ shortage, highlighting a clinical imperative for alternative therapeutic strategies. Recent advances in pluripotent stem cell-derived kidney organoids, exhibiting multicellular complexity and aspects of renal structure and function, support their use as an innovative source of functional nephrons for organ repair/replacement strategies. Translation will require the ability to reliably scale organoid production, pattern tissue geometry, establish functional vasculature, and promote developmental maturation in vitro. We have developed an innovative approach to bioengineering kidney by integrating stem cell biology, 3D biofabrication, primary human microvessels, and whole tissue perfusion to generate vascularized, anatomically patterned human kidney tissues. Here we show that exposure of biofabricated kidney tissues to flow/shear stress promotes nephron maturation in vitro, characterized by improved cellular organization of developing glomeruli, with expansion of Bowman’s space, as well as increased renal tubule lumenization, polarization, and transporter expression. Additionally, we demonstrate that incorporation of human microvessels, in combination with perfusion culture, leads to high density tissue vascularization, with evidence of glomerular wrapping by endothelial cells, capillary invasion, and formation of vascular structures with patent lumens. These findings mark a significant advancement in the field of renal tissue engineering, demonstrating the feasibility of scaling kidney organoids into vascularized, patterned tissues with functional potential.
Funding Source: This work is supported by Wellcome Leap funding as part of the HOPE Program.
