Abstract
De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection1 and tumor metastasis2,3. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.
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Acknowledgements
This work was supported in part by the European Union 5th Framework Project “Chronic Kidney Disease” (QLG1-CZ-2000-00619), the 6th Framework Integrated Project “Lymphangiogenomics” (LSGH-2004-503573) and from the Center of Excellence for Clinical and Experimental Oncology (CLEXO) to D.K. We are indebted to K.H. Müller-Hermelink and H. Einsele, University Würzburg, and B. Bültmann, University Tübingen, for their help in allocating the archival tumor tissue blocks.
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Supplementary information
Supplementary Table 1
Number of sex chromosomes in cells of renal transplants. (PDF 12 kb)
Supplementary Table 2
Colocalization of the proliferation marker MIB-1 in Prox-1+ nuclei. (PDF 12 kb)
Supplementary Table 3
Id-1–expressing lymphatic endothelial cells in renal transplants. (PDF 16 kb)
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Kerjaschki, D., Huttary, N., Raab, I. et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12, 230–234 (2006). https://doi.org/10.1038/nm1340
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DOI: https://doi.org/10.1038/nm1340
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