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Kidney Side Population Reveals Multilineage Potential and Renal Functional Capacity but also Cellular Heterogeneity

Grant A. Challen^*,, Ivan Bertoncello, James A. Deane, Sharon D. Ricardo and Melissa H. Little^*

^* Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland; The Peter MacCallum Cancer Centre and Department of Pathology, University of Melbourne, Melbourne; Monash Immunology and Stem Cell Laboratories, Monash University, Melbourne, Australia; and Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas

Address correspondence to: Prof. Melissa H. Little, Institute for Molecular Bioscience, Queensland Bioscience Precinct, 306 Carmody Road, The University of Queensland, St. Lucia, Brisbane, QLD, 4072, Australia. Phone: +61-7-3346-2054; Fax: +61-7-3346-2101; M.Little{at}imb.uq.edu.au

Received for publication December 4, 2005. Accepted for publication April 9, 2006.

Side population (SP) cells in the adult kidney are proposed to represent a progenitor population. However, the size, origin, phenotype, and potential of the kidney SP has been controversial. In this study, the SP fraction of embryonic and adult kidneys represented 0.1 to 0.2% of the total viable cell population. The immunophenotype and the expression profile of kidney SP cells was distinct from that of bone marrow SP cells, suggesting that they are a resident nonhematopoietic cell population. Affymetrix expression profiling implicated a role for Notch signaling in kidney SP cells and was used to identify markers of kidney SP. Localization by in situ hybridization confirmed a primarily proximal tubule location, supporting the existence of a tubular "niche," but also revealed considerable heterogeneity, including the presence of renal macrophages. Adult kidney SP cells demonstrated multilineage differentiation in vitro, whereas microinjection into mouse metanephroi showed that SP cells had a 3.5- to 13-fold greater potential to contribute to developing kidney than non-SP main population cells. However, although reintroduction of SP cells into an Adriamycin-nephropathy model reduced albuminuria:creatinine ratios, this was without significant tubular integration, suggesting a humoral role for SP cells in renal repair. The heterogeneity of the renal SP highlights the need for further fractionation to distinguish the cellular subpopulations that are responsible for the observed multilineage capacity and transdifferentiative and humoral activities.

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