Characterizing Renal Interstitial Heterogeneity and Its Role in Nephron Patterning
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Chronic kidney disease (CKD) is a growing national health concern affecting 30 million Americans. CKD can lead to permanent loss of kidney function requiring treatment for survival, yet the only two treatment options, dialysis and transplant, are unable to meet the needs of the millions impacted. There are numerous efforts to engineer renal replacement therapy tissue yet most focus primarily on the nephron (the functional unit of the kidney) and the vasculature. Although these efforts are exciting, they face two significant obstacles. First, current progenitor cell-based technologies have only produced relatively immature tissues. Second, most efforts have overlooked the importance of renal stroma, a cell type that not only impacts the development of the renal parenchyma, but which also plays a crucial role in kidney physiology as well as having multiple endocrine functions. Using a combination of single-cell ribonucleic acid sequencing (scRNA-seq) and messenger RNA (mRNA) in situ hybridization we have found that the mouse embryonic renal stroma is a molecularly heterogeneous population of cells with different cell types occupying anatomically distinct positions that correlate with anatomically and functionally distinct regions of the adjacent parenchyma. We find that human fetal kidney interstitium shows a similar degree of heterogeneity to the mouse extending this phenomenon beyond our model system. Further, we find that beta-catenin has a cell-autonomous role in the development of a medullary subset of the interstitium and that this non-autonomously affects the development of the adjacent tissue. These data suggest stromal sub-types establish unique microenvironmental niches that provide signals which regulate the differentiation/segmentation of the nephron. We find that interstitial heterogeneity is evident at the earliest stages of renal development, and that interstitial patterning develops independent of signals from the nephron tubules. Using a novel nephrogenic zone cell differentiation assay, we find a subpopulation preferentially promotes proximal tubule differentiation and non-autonomously promotes proliferation. These data highlight a functional role of the renal interstitium in renal development that cannot be ignored in current renal regeneration efforts.
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The file named "ENGLAND-PRIMARY-2022-1.pdf" is the primary dissertation file. Four (4) supplemental video files and one (1) Micosoft Excel file are also available and may be viewed individually.