Generation of Human Glomerular Endothelial Cells for Kidney Disease Research and Treatment

Background & Unmet Need

• >800 million people worldwide suffer from chronic kidney disease1, which can progress to end-stage renal disease, requiring dialysis or transplantation
• Many patients with end-stage renal disease undergo complications related to hemodialysis, such as infection, or never receive a kidney transplant
• Kidney organoids could provide an avenue for development of new therapeutics for renal disease, but the heterogeneity of kidney vasculature is a major hurdle for their generation
• The kidney is vascularized with highly specialized and zonated (region-specific) endothelial cells that are essential for its filtration functions, including glomerular endothelial cells
• Unmet Need: Methods for generating functional kidney vasculature and tissue for research and therapeutic purposes

Technology Overview

• The Technology: Method to reprogram human umbilical vein endothelial cells (HUVECs) into human glomerular endothelial cells (HGECs) by expressing the transcription factor Tbx3
• Tbx3 can be used alone or in combination with additional transcription factors—Prdm1, Gata5, and Pbx1—with the best results observed when all four factors are co-expressed
• HGECs could, for example, be co-cultured with kidney podocytes and mesangial cells to construct functional glomeruli
• The Discovery: Tbx3 was identified as a crucial mediator of glomerular development and function through high-throughput bulk single-cell RNA sequencing of kidney vasculature
• PoC Data: Overexpression of Tbx3, alone or in combination with Prdm1, Gata5, and Pbx1, in HUVECs results in gene expression profiles that closely match those found in the human glomerulus

Technology Applications

• Co-culture of HGECs with kidney podocytes and mesangial cells to construct functional glomeruli
• Use of HGECs in high throughput screening for chronic kidney disease drug discovery
• Use of HGECs to build vascularized kidney organoids to model functions of the kidney
• Therapeutic transplantation of HGECs or functional glomeruli to regenerate damaged kidney tissue

Technology Advantages

• HUVECs are readily obtainable as a starting source for HGEC generation
• Flexibility in the methodology used to overexpress Tbx3, Prdm1, Pbx1, and/or Gata1

Immunofluorescent staining in human kidney tissue confirms that Tbx3 protein (green) is restricted to endothelial cells in glomerular capillaries