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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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          Most cited references 14

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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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              Dog peritoneal and pleural cavities as bioreactors to grow autologous vascular grafts.

              The purpose of this study was to grow "artificial blood vessels" for autologous transplantation as arterial interposition grafts in a large animal model (dog). Tubing up to 250 mm long, either bare or wrapped in biodegradable polyglycolic acid (Dexon) or nonbiodegradable polypropylene (Prolene) mesh, was inserted in the peritoneal or pleural cavity of dogs, using minimally invasive techniques, and tethered at one end to the wall with a loose suture. After 3 weeks the tubes and their tissue capsules were harvested, and the inert tubing was discarded. The wall of living tissue was uniformly 1-1.5 mm thick throughout its length, and consisted of multiple layers of myofibroblasts and matrix overlaid with a single layer of mesothelium. The myofibroblasts stained for alpha-smooth muscle actin, vimentin, and desmin. The bursting strength of tissue tubes with no biodegradable mesh scaffolds was in excess of 2500 mm Hg, and the suture holding strength was 11.5 N, both similar to that in dog carotid and femoral arteries. Eleven tissue tubes were transplanted as interposition grafts into the femoral artery of the same dog in which they were grown, and were harvested after 3 to 6.5 months. Eight remained patent during this time. At harvest, their lumens were lined with endothelium-like cells, and wall cells stained for alpha-actin, smooth muscle myosin, desmin and smoothelin; there was also a thick "adventitia" containing vasa vasorum. Peritoneal and pleural cavities of large animals can function as bioreactors to grow myofibroblast tubes for use as autologous vascular grafts.
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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
                © 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.

                Page count
                Figures: 4, Tables: 1, References: 26, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/87939
                Categories
                Original Paper

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