Chronic kidney disease is a growing problem in the industrialized world. Despite advances, treatment of chronic conditions relies on replacement of kidney function by dialysis and eventually transplantation. Availability of organs for transplantation is limited, and alternative sources of kidney tissue are needed. Recent work highlighting the potential of embryonic kidney tissue to form nephrons in the adult indicates that regenerative therapies for kidney disease may be feasible. Furthermore, transplantation of embryonic tissue is associated with low allogeneic reactivity, minimizing the need for immunosuppressive therapy of transplant recipients. We thus believe that regenerative therapy using embryonic progenitors is a realistic goal as an alternative to transplantation. However, little is known about the nephron progenitor cell, and its requirements for ex vivo expansion. Recently, the PI has identified a cell-type within the embryonic kidney that acts as a nephrogenic precursor in vivo. This progenitor cell is maintained in a complex cellular environment, in which signals regulating proliferation and differentiation are finely balanced. This micro-environment is created largely by the hitherto poorly understood peripheral stroma of the developing kidney. Preliminary studies demonstrate that the TGF? superfamily growth factor BMP7, secreted from nephron progenitor cells, signals to neighboring peripheral stroma. We find that the interpretation of BMP signaling is influenced by expression of the transcription factor Foxd1 in cells of peripheral stroma, indicating reciprocal interplay between these two cells to establish a cellular niche for maintenance of the nephron progenitor. Our hypothesis is that embryonic nephrogenic precursors isolated using our marking system will be an excellent candidate for de novo nephrogenesis. Our work aims to understand the signaling environment required for maintenance of these cells in an undifferentiated state to enable isolation and expansion of nephrogenic precursors for the purpose of engraftment.
Specific aims are to: i) Define the role of the stromal Foxd1 transcription factor in BMP and TGF? signal transduction, ii) Characterize the developmental potential of peripheral stroma and iii) Inactivate TGF? superfamily signaling in peripheral stroma by conditionally activating components of the signal transduction pathway. The rapidly advancing field of regenerative medicine has great potential to address unmet therapeutic needs in chronic kidney disease. For cell-based therapies to become reality we must understand the signals regulating renewal and differentiation of the progenitor cells that constitute the building blocks of the functional kidney. The proposed study aims to define the signaling environment governing self-renewal of embryonic nephron progenitors, a cell-type of great potential in cell-based therapy for renal disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Hoshizaki, Deborah K
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Maine Medical Center
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Oxburgh, Leif; Muthukrishnan, Sree Deepthi; Brown, Aaron (2017) Growth Factor Regulation in the Nephrogenic Zone of the Developing Kidney. Results Probl Cell Differ 60:137-164
Brown, Aaron C; Muthukrishnan, Sree Deepthi; Oxburgh, Leif (2015) A synthetic niche for nephron progenitor cells. Dev Cell 34:229-41
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Brown, Aaron C; Muthukrishnan, Sree Deepthi; Guay, Justin A et al. (2013) Role for compartmentalization in nephron progenitor differentiation. Proc Natl Acad Sci U S A 110:4640-5
Kirov, Aleksandr; Duarte, Maria; Guay, Justin et al. (2012) Transgenic expression of nonclassically secreted FGF suppresses kidney repair. PLoS One 7:e36485
Brown, Aaron C; Adams, Derek; de Caestecker, Mark et al. (2011) FGF/EGF signaling regulates the renewal of early nephron progenitors during embryonic development. Development 138:5099-112

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