Modeling Diabetic Kidney Fibrosis with Kidney Organoids derived from Human Pluripotent Stem Cells
We have established a highly efficient and specific protocol for generation of SIX2+ nephron progenitor cells (NPCs) and kidney organoids consisting of podocytes, proximal tubules, loops of Henle, distal tubules, and connecting tubules/collecting ducts with interstitial cells, from human pluripotent stem cells (hPSCs). This novel technology represents additional systems for studies of kidney diseases and regeneration. Chronic kidney disease (CKD) is a worldwide health care problem and diabetic kidney disease is the major cause for CKD. To develop targeted therapies for CKD caused by diabetes, it is vital to understand underlining molecular mechanisms. Kidney organoids derived from hPSCs can be a novel tool to study mechanisms of fibrosis in human tissues; however, little is known about modeling kidney fibrosis with organoids. Tubulointerstitial crosstalk contributes to development of kidney fibrosis, and damage to tubular cells leads to profibrotic phenotypes of tubules characterized by dedifferentiation, cell cycle arrest, and profibrotic cytokine production. The origin of myofibroblasts includes local resident fibroblasts, bone marrow, and pericytes. The human stem cell-derived organoids consist of multi-cellular compartments including nephron epithelial cells, vascular cells, and interstitial stromal cells including fibroblasts and pericytes in 3-dimensional structures, and our previous work demonstrated cisplatin-induced injury to LTL+ proximal tubules, but not to podocytes or interstitial cells. These facts led us to hypothesize that kidney organoids can be used to study tubulointerstitial cross talk implicated in kidney fibrosis, with nephrotoxicants specific to proximal tubules (Aim 1). In addition, our preliminary experiment demonstrated upregulation of CTGF, a profibrotic cytokine, in organoids with high glucose treatment, leading us to hypothesize that high glucose treatment exacerbates the profibrotic phenotype of tubular epithelial cells when exposed to nephrotoxicants (Aim 2). With this pilot study, we anticipate that the human stem cell-derived organoids would provide a novel platform to study mechanisms of kidney fibrosis in human cells, expecting to find clues to understand molecular mechanisms of how diabetes mellitus exacerbates kidney fibrosis through profibrotic induction in tubular cells.

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