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Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants

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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Figure 1: Localization of lymphatic vessels by immunohistochemistry using antibodies to podoplanin in normal human renal cortex from a tumor nephrectomy (a), and in an explanted kidney (subject NTX 11316/04) of a male recipient and a female donor (b).
Figure 2: Distribution of lymphatic vessels in post-transplant carcinomas arising in recipients of gender-mismatched bone marrow transplants.
Figure 3: Isolation and in vitro differentiation of VEGFR-3+ monocytes.

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References

  1. Kerjaschki, D. et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15, 603–612 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Saharinen, P., Tammela, T., Karkkainen, M.J. & Alitalo, K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 25, 387–395 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Schoppmann, S. et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am. J. Pathol. 161, 947–956 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Tepper, O.M. et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood 105, 1068–1077 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27–31 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Shaked, Y. et al. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7, 101–111 (2005).

    CAS  PubMed  Google Scholar 

  7. Hong, Y.K. et al. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev. Dyn. 225, 351–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Mazal, P.R. et al. Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients. N. Engl. J. Med. 347, 653–659 (2002).

    Article  PubMed  Google Scholar 

  9. Breiteneder-Geleff, S. et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am. J. Pathol. 154, 385–394 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jackson, D.G. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 112, 526–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Rafii, S. & Lyden, D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat. Med. 9, 702–712 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Asahara, T. et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 18, 3964–3972 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Benezra, R., Rafii, S. & Lyden, D. The Id proteins and angiogenesis. Oncogene 20, 8334–8341 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Salven, P. et al. VEGFR-3 and CD133 identify a population of CD34+ lymphatic/vascular endothelial precursor cells. Blood 101, 168–172 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Ito, W.D. & Khmelevski, E. Tissue macrophages: “satellite cells” for growing collateral vessels? A hypothesis. Endothelium 10, 233–235 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Maruyama, K. et al. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J. Clin. Invest. 115, 2363–2372 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kerjaschki, D. The crucial role of macrophages in lymphangiogenesis. J. Clin. Invest. 115, 2316–2319 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rajantie, I. et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104, 2084–2086 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. He, Y. et al. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res. 64, 3737–3740 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Plunkett, M. et al. Rosetting of activated human T lymphocytes with autologous erythrocytes. Definition of the receptor and ligand molecules as CD2 and lymphocyte function-associated antigen (LFA-3). J. Exp. Med. 165, 664–676 (1987).

    Article  CAS  PubMed  Google Scholar 

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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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Correspondence to Dontscho Kerjaschki.

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The authors declare no competing financial interests.

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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