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      Call for Papers: Green Renal Replacement Therapy: Caring for the Environment

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      Establishment of Metanephros Transplantation in Mice Highlights Contributions by Both Nephrectomy and Pregnancy to Developmental Progression

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          Abstract

          Background: It has been demonstrated that embryonic kidneys (metanephroi) xenotransplanted into the omentum of adult recipients continue to develop and display immune protection due to their more naïve immune presentation. To date, this has been achieved using rat, pig and human metanephroi, with unilateral nephrectomy (UNX) of recipient rats a requisite of renal development. The aim of this study was to adapt this approach for use in mice and examine the parameters affecting successful onward development in this species. Methods: Metanephroi at embryonic age (E) 13.5 were transplanted either onto the body wall, abdominal fat pads or omentum of recipient isogenic C57/Bl6 mice using either sutures or polyglycolic acid mesh. Having established greatest success with polyglycolic acid mesh on the body wall, E12.5 and 15.5 days metanephroi from C57/Bl6 mice were then transplanted onto the body wall of control (non-pregnant non-UNX), UNX or 12.5 days post-coitum pregnant isogenic recipients. After 7 days, implanted tissue was harvested and examined using histology and immunohistochemistry for markers of renal maturation. The mean number of S-shaped bodies and glomeruli per section were recorded and statistically analysed for significant differences between all recipient groups and untransplanted metanephroi. The degree of development was scored qualitatively. Results: Transplanted E12.5 metanephroi developed S-shaped bodies and glomeruli in all recipient groups, although there were statistically higher numbers of S-shaped bodies in UNX (n = 2) and pregnant recipients (n = 9) than in control recipients (n = 4). Continued development, as indicated by mature vascularized glomeruli, was only observed in those E15.5 metanephroi transplanted into pregnant recipients (n = 11) with a 15.5-fold increase in S-shaped bodies and 4-fold increase in glomeruli compared with control transplants (n = 12). Conclusions: We have successfully established metanephros transplantation in mice and demonstrated enhancement of onward development of E12.5 metanephroi in response to both pregnancy and UNX. Using E15.5 metanephroi, continued development only occurred in pregnant recipients, implying pregnancy provides an environment conducive to continued organogenesis. This murine assay, when coupled with transgenically-tagged strains of mice, will allow the investigation of the relative contribution of donor and recipient cells to this process.

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          Human and porcine early kidney precursors as a new source for transplantation.

          Kidney transplantation has been one of the major medical advances of the past 30 years. However, tissue availability remains a major obstacle. This can potentially be overcome by the use of undifferentiated or partially developed kidney precursor cells derived from early embryos and fetal tissue. Here, transplantation in mice reveals the earliest gestational time point at which kidney precursor cells, of both human and pig origin, differentiate into functional nephrons and not into other, non-renal professional cell types. Moreover, successful organogenesis is achieved when using the early kidney precursors, but not later-gestation kidneys. The formed, miniature kidneys are functional as evidenced by the dilute urine they produce. In addition, decreased immunogenicity of the transplants of early human and pig kidney precursors compared with adult kidney transplants is demonstrated in vivo. Our data pinpoint a window of human and pig kidney organogenesis that may be optimal for transplantation in humans.
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            Transplantation of developing metanephroi into adult rats.

            Transplantation of developing metanephroi into adult hosts has been proposed as a means to augment host renal function. We implanted whole metanephroi from embryonic day 15 (E15) rats subcapsularly in kidneys or into the omentum of non-immunosupressed adult rat hosts. At the time of implantation, some host rats underwent unilateral nephrectomy (UNX) or unilateral nephrectomy and partial contralateral renal infarction (1 1/2 NX). E15 metanephroi contained only metanephric blastema, segments of ureteric bud, and primitive nephrons with no glomeruli. Four to six weeks post-implantation, metanephroi from E15 rats had enlarged, become vascularized, and had formed mature tubules and glomeruli. Ureters of metanephroi transplanted into the omentum were anastomosed to hosts' ureters that remained after UNX. Four weeks following ureteroureterostomy, the contralateral kidney was removed. Inulin clearances of seven metanephroi implanted into UNX hosts averaged 0.11 +/- 0.02 microliters/min/100 g (2.42 +/- 0.70 microliters/min/g kidney wt) and the creatinine clearances averaged 0.65 +/- 0.18 microliters/min/100 g. Metanephroi weighed 71 +/- 15 mg (approximately 4% of the contralateral native kidney). The transplanted metanephroi were vascularized by arteries originating from the omentum. Both weights of transplanted metanephroi (145 +/- 24 mg) and inulin clearances of transplanted metanephroi (30.1 +/- 8.7 microliters/min/g kidney weight) were significantly increased in rats that underwent 1 1/2 NX compared to UNX. In contrast, transplantation of developed kidneys resulted in rejection. Our findings establish that functional chimeric kidneys develop from metanephroi transplanted in adult hosts.
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              Expression of hepatocyte growth factor and its receptor c-met in the ovine uterus.

              Epithelial-mesenchymal interactions (EMI) are necessary for epithelial cell proliferation, differentiation, and function in the uterus and are mediated, in part, by paracrine growth factors of stromal origin. The objective of this study was to determine if hepatocyte growth factor (HGF, scatter factor) and its receptor c-met were present in the ovine uterus and to characterize their temporal and spatial expression during the estrous cycle and pregnancy. Reverse transcription-polymerase chain reaction was used to clone partial cDNAs for ovine HGF and c-met from endometrial total RNA. Northern blot analysis of endometrial RNA revealed expression of a 6-kb mRNA for HGF and an 8-kb mRNA for c-met in ovine endometrium. In situ hybridization demonstrated that HGF mRNA was expressed by stromal cells of the endometrium, whereas c-met mRNA was localized exclusively to luminal and glandular epithelial cells. In the early conceptus, HGF mRNA was expressed by chorioallantoic mesenchyme, and c-met was expressed by trophectoderm. Steady-state levels of endometrial c-met mRNA increased after Day 9 in both cyclic and pregnant ewes. The HGF mRNA was expressed during both the estrous cycle and early pregnancy. Results indicate that HGF is a stromal-derived paracrine growth factor in the ovine uterus and placenta that is potentially involved in endometrial epithelial-stromal interactions and chorioallantoic stromal-trophectodermal interactions. In the ovine uterus, HGF may stimulate epithelial morphogenesis and differentiated function required for establishment and maintenance of pregnancy, conceptus implantation, and placentation.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2005
                December 2005
                01 September 2005
                : 101
                : 4
                : e155-e164
                Affiliations
                aInstitute for Molecular Bioscience and bCentre for Research in Vascular Biology, School of Biomedical Sciences, The University of Queensland, St. Lucia, and cWesley Research Institute, Toowong, Australia
                Article
                87939 Nephron Exp Nephrol 2005;101:e155–e164
                10.1159/000087939
                16131810
                2c9c420a-23d7-44d4-92e2-2339c137d733
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 22 December 2004
                : 08 June 2005
                Page count
                Figures: 4, Tables: 1, References: 26, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Xenotransplantation,Kidney development,Metanephric transplantation

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