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Tissue-Specific Stem Cells
Version of Record online: 2 AUG 2010
Copyright © 2010 AlphaMed Press
Volume 28, Issue 9, pages 1674–1685, September 2010
How to Cite
Lasagni, L., Ballerini, L., Angelotti, M. L., Parente, E., Sagrinati, C., Mazzinghi, B., Peired, A., Ronconi, E., Becherucci, F., Bani, D., Gacci, M., Carini, M., Lazzeri, E. and Romagnani, P. (2010), Notch Activation Differentially Regulates Renal Progenitors Proliferation and Differentiation Toward the Podocyte Lineage in Glomerular Disorders. STEM CELLS, 28: 1674–1685. doi: 10.1002/stem.492
Author contributions: L.L.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; L.B., M.L.A., E.P., C.S., B.M., A.P., E.R., F.B., D.B., M.G., M.C., and E.L.: collection and assembly of data, data analysis and interpretation; P.R.: conception and design, data interpretation, financial support, manuscript writing, final approval of manuscript.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS August 2, 2010. Available online without subscription through the open access option.
- Issue online: 2 AUG 2010
- Version of Record online: 2 AUG 2010
- Manuscript Accepted: 22 JUL 2010
- Manuscript Received: 18 MAY 2010
- European Community under the European Community's Seventh Framework Programme. Grant Numbers: FP7/2007-2013, 223007
- European Research Council Starting Grant under the European Community's Seventh Framework Programme. Grant Number: FP7/2007-2013
- ERC. Grant Number: 205027
- Tuscany Ministry of Health
- Italian Ministry of University (MIUR)
- Associazione Italiana per la Ricerca sul Cancro
- Renal stem cells;
- Renal progenitors;
Glomerular diseases account for 90% of end-stage kidney disease. Podocyte loss is a common determining factor for the progression toward glomerulosclerosis. Mature podocytes cannot proliferate, but recent evidence suggests that they can be replaced by renal progenitors localized within the Bowman's capsule. Here, we demonstrate that Notch activation in human renal progenitors stimulates entry into the S-phase of the cell cycle and cell division, whereas its downregulation is required for differentiation toward the podocyte lineage. Indeed, a persistent activation of the Notch pathway induced podocytes to cross the G2/M checkpoint, resulting in cytoskeleton disruption and death by mitotic catastrophe. Notch expression was virtually absent in the glomeruli of healthy adult kidneys, while a strong upregulation was observed in renal progenitors and podocytes in patients affected by glomerular disorders. Accordingly, inhibition of the Notch pathway in mouse models of focal segmental glomerulosclerosis ameliorated proteinuria and reduced podocyte loss during the initial phases of glomerular injury, while inducing reduction of progenitor proliferation during the regenerative phases of glomerular injury with worsening of proteinuria and glomerulosclerosis. Taken altogether, these results suggest that the severity of glomerular disorders depends on the Notch-regulated balance between podocyte death and regeneration provided by renal progenitors. STEM CELLS 2010; 28:1674–1685.