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. ? ? ?
| Muthukrishnan, Sree Deepthi; Ryzhov, Sergey; Karolak, Michele et al. (2018) Nephron progenitor cell death elicits a limited compensatory response associated with interstitial expansion in the neonatal kidney. Dis Model Mech 11: |
| 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 |
| 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 |
| Oxburgh, Leif; Rosen, Clifford J (2017) New Insights into Fuel Choices of Nephron Progenitor Cells. J Am Soc Nephrol 28:3133-3135 |
| Caron, Jennifer M; Ames, Jacquelyn J; Contois, Liangru et al. (2016) Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope. Am J Pathol 186:1649-61 |
| Brown, Aaron C; Muthukrishnan, Sree Deepthi; Oxburgh, Leif (2015) A synthetic niche for nephron progenitor cells. Dev Cell 34:229-41 |
| Muthukrishnan, Sree Deepthi; Yang, Xuehui; Friesel, Robert et al. (2015) Concurrent BMP7 and FGF9 signalling governs AP-1 function to promote self-renewal of nephron progenitor cells. Nat Commun 6:10027 |
| Yang, Xuehui; Liaw, Lucy; Prudovsky, Igor et al. (2015) Fibroblast growth factor signaling in the vasculature. Curr Atheroscler Rep 17:509 |
| Guay, Justin A; Wojchowski, Don M; Fang, Jing et al. (2014) Death associated protein kinase 2 is expressed in cortical interstitial cells of the mouse kidney. BMC Res Notes 7:345 |
| Fetting, Jennifer L; Guay, Justin A; Karolak, Michele J et al. (2014) FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney. Development 141:17-27 |
Showing the most recent 10 out of 23 publications
