Approximately 1,000,000 Americans have end state renal disease and these numbers are increasing. Dialysis provides an essential but unsatisfactory palliative solution with high morbidity and high mortality. A kidney transplant can restore kidney function, but the number of transplants is insufficient for the patient population, and the numbers have not increased significantly over the last 20 years. Several groups have demonstrated the directed differentiation of kidney-like structures, kidney organoids, from mouse and human pluripotent stem cells. These advances highlight the need to generate an enhanced understanding of the critical processes underlying mammalian nephrogenic programs. Further, recent advances in our understanding of human kidney development from the McMahon group emphasize the importance of direct human studies. Consequently, we combine analysis across developing mouse and human kidney systems with human kidney organoids to examine key regulatory processes in the nephrogenic program.
In Specific Aim 1, we will determine the epigenetic control mechanisms regulating normal mouse and human nephron progenitor states through extensive analysis of RNA-seq, ChIP-seq, ATAC-seq and HI-C datasets. The regulatory processes identified through these studies are interesting in their own right but serve also as a critical benchmark for in vitro efforts to generate normal nephron progenitor cells.
In Specific Aim 2, we will determine the transcriptional mechanisms of Wnt/-catenin pathway mediated maintenance and commitment of nephron progenitor cells. Wnt signaling plays a central role in stem/progenitor regulation in a variety of organ systems. Recent advances in nephron progenitor culture and differentiation make the kidney an attractive model for unravelling the duality of Wnt pathway action on nephron progenitor cells.
In Specific Aim 3, we will examine the role of canonical Wnt signaling in distal patterning of the developing nephron. In patterning the early nephron anlagen, several lines of evidence links Notch and Wnt signaling to proximal and distal fate-specification, respectively. We will examine the role of Wnt-signaling in distal development using human and optimized human pluripotent cell kidney organoid model system, genetically engineered to report on nephron patterning events. The anticipated research outcomes will identify critical regulatory mechanisms governing the maintenance, commitment and differentiation of stem/progenitor cell types of broad interest to researchers working across different organ systems. The studies will also enhance our understanding of human kidney development and educate effective therapeutic application of stem cell-derived kidney structures.
Approximately 1,000,000 Americans have end state renal disease and these numbers are increasing. The functional unit of the kidney is the nephron and this proposal focuses on developing a deep understanding of processes regulating, maintaining and differentiating mouse and human nephron-forming progenitor cells. The findings will provide new insight into stem/progenitor control processes of broad relevance across organ systems and accelerate therapeutic-focused efforts to direct human stem cells to normal kidney structures.
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|Ramalingam, Harini; Fessler, Alicia R; Das, Amrita et al. (2018) Disparate levels of beta-catenin activity determine nephron progenitor cell fate. Dev Biol 440:13-21|
|Naiman, Natalie; Fujioka, Kaoru; Fujino, Mari et al. (2017) Repression of Interstitial Identity in Nephron Progenitor Cells by Pax2 Establishes the Nephron-Interstitium Boundary during Kidney Development. Dev Cell 41:349-365.e3|
|Rutledge, Elisabeth A; Benazet, Jean-Denis; McMahon, Andrew P (2017) Cellular heterogeneity in the ureteric progenitor niche and distinct profiles of branching morphogenesis in organ development. Development 144:3177-3188|
|O'Brien, Lori L; Guo, Qiuyu; Lee, YoungJin et al. (2016) Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators. Development 143:595-608|
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|Kobayashi, Akio; Mugford, Joshua W; Krautzberger, A Michaela et al. (2014) Identification of a multipotent self-renewing stromal progenitor population during mammalian kidney organogenesis. Stem Cell Reports 3:650-62|
|Little, Melissa H; Brown, Dennis; Humphreys, Benjamin D et al. (2014) Defining kidney biology to understand renal disease. Clin J Am Soc Nephrol 9:809-11|
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