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Engraftment and Differentiation of Human Metanephroi into Functional Mature Nephrons after Transplantation into Mice Is Accompanied by a Profile of Gene Expression Similar to Normal Human Kidney Development

Benjamin Dekel^*, Ninette Amariglio, Naftali Kaminski, Arnon Schwartz, Elinor Goshen, Fabian D. Arditti, Ilan Tsarfaty^||, Justen H. Passwell^*, Yair Reisner and Gideon Rechavi

Departments of *Pediatrics, Pediatric Hemato-oncology and Functional Genomics Unit, and Nuclear Medicine, Sheba Medical Center, Tel Hashomer, Israel; Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and ^||Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Correspondence to Dr. Benjamin Dekel, Department of Pediatrics, Sheba Medical Center, Tel Hashomer, Israel 52621. Phone: 972-3-530-2445; Fax: 972-8-9344141; E-mail: bmdekel{at}wicc.weizmann.ac.il

ABSTRACT. Metanephroi, the embryonic precursors of the adult kidney, can be induced in vivo to grow and develop. Despite their potential clinical utility for transplantation, the ability of human metanephroi to differentiate after transplantation into functional mature nephrons is mostly unknown. To address this, 70-d human metanephroi were transplanted into NOD/SCID mice; global gene expression patterns that underlie development of human metanephric transplants were analyzed and compared with normal human kidney development. In addition, functionality of the grafts was assessed by dimercaptosuccinic acid radioisotope scans at different times after transplantation. The results of hybridization to cDNA arrays when RNA was derived from normal human kidneys at 8, 12, 16, and 20 wk gestation demonstrated that a subset of 240 genes changed substantially with time. The induced genes can be classified as cell cycle regulators, transcription and growth factors, and signaling, transport, adhesion, and extracellular matrix molecules. Strikingly, clustering analysis of global gene expression at 2, 6, and 10 wk after metanephric transplantation revealed an expression profile that characterizes normal human kidney development. Moreover, maturation of the transplants was accompanied by an increased uptake of dimercaptosuccinic acid. Nevertheless, expression levels of specific genes were mostly found to be suppressed in the transplants compared with the normal kidneys. These data provide insights into human kidney development and support the possibility of the transplantability of human metanephroi. Understanding of the molecular regulation of the transplanted developing metanephroi might lead to the development of strategies aimed at increasing the levels of specific genes, nephron endowment, and graft function.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673