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Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1

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      Abstract

      There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover.

      Author Summary

      It is important to understand the cellular and molecular pathways that regulate the maintenance and turnover of adult tissues. These processes often go awry in diseases and are likely to deteriorate with ageing. Here we show that removal of a single gene, the Wilms' Tumour gene, Wt1, in the adult mouse leads to the extremely rapid deterioration of multiple tissues. Within 7–9 days after gene removal kidneys fail, the pancreas and spleen suffer severe atrophy, there is widespread loss of bone and body fat, and red blood cells are no longer produced. Our findings reveal the vulnerability of adult tissues, while opening up avenues for dissecting the pathways controlling tissue turnover. Further experiments showed that the tissue failure we observed is due both to local defects of stem/progenitor cell activities and to significant changes in the serum levels of some key master regulators. In particular there is a dramatic reduction in the levels of IGF-1, a key regulator of homeostasis and aging. Our studies also show that the control of adult tissue turnover may be different from that during foetal development. These findings have important implications for understanding and treating common human diseases.

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      Most cited references 56

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      The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.
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        Osteoblastic cells regulate the haematopoietic stem cell niche.

        Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.
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          Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.

          The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of clonogenic skeletal progenitors found in BM stroma, has long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendothelial cells within a miniature bone organ. Establishment of subendothelial stromal cells in developing heterotopic BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Subendothelial stromal cells residing on the sinusoidal wall are major producers of Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of skeletal progenitors in BM sinusoids, and angiogenesis.
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            Author and article information

            Affiliations
            [1 ]Medical Research Council Human Genetics Unit and the Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom
            [2 ]Queen's Medical Research Institute, Edinburgh, United Kingdom
            [3 ]Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom
            [4 ]Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
            [5 ]Institute of Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, Edinburgh, United Kingdom
            [6 ]The Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
            [7 ]Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom
            [8 ]Scottish National Blood Transfusion Service, Centre for Regenerative Medicine, Edinburgh, United Kingdom
            [9 ]Molecular Medicine Centre and the Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, United Kingdom
            University of Oxford, United Kingdom
            Author notes

            Conceived and designed the experiments: Y-YC NH KS RvH NB-V. Performed the experiments: Y-YC DB HM EF DS NM AT RB RvH NB-V. Analyzed the data: Y-YC NH DB KS EF W-CL RvF NM DS NB-V CN SEJ. Contributed reagents/materials/analysis tools: Y-YC PP NM EF KS RvH NB-V CN. Wrote the paper: Y-YC NH RvH. Maintained the animal colony: PH.

            Contributors
            Role: Editor
            Journal
            PLoS Genet
            plos
            plosgen
            PLoS Genetics
            Public Library of Science (San Francisco, USA )
            1553-7390
            1553-7404
            December 2011
            December 2011
            22 December 2011
            : 7
            : 12
            22216009
            3245305
            PGENETICS-D-11-00778
            10.1371/journal.pgen.1002404
            (Editor)
            Chau et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 16
            Categories
            Research Article
            Biology
            Anatomy and Physiology
            Developmental Biology
            Genetics
            Histology
            Immunology
            Model Organisms
            Molecular Cell Biology
            Proteomics

            Genetics

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