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  • 1.
    Alvarez, Alberto
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Daubel, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, C.
    Uppsala Univ, Dept Immunol Genet & Pathol, Rudbeck Lab, Dag Hammarskjoldsvag 20, S-75185 Uppsala, Sweden;Karolinska Inst, ICMC, Dept Med Huddinge, Novum, Blickagangen 6, S-14157 Huddinge, Sweden.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Gängel, Konstantin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tamoxifen-independent recombination of reporter genes limits lineage tracing and mosaic analysis using CreER(T2) lines2019In: Transgenic research, ISSN 0962-8819, E-ISSN 1573-9368Article in journal (Refereed)
    Abstract [en]

    The CreER(T2)/loxP system is widely used to induce conditional gene deletion in mice. One of the main advantages of the system is that Cre-mediated recombination can be controlled in time through Tamoxifen administration. This has allowed researchers to study the function of embryonic lethal genes at later developmental timepoints. In addition, CreER(T2) mouse lines are commonly used in combination with reporter genes for lineage tracing and mosaic analysis. In order for these experiments to be reliable, it is crucial that the cell labeling approach only marks the desired cell population and their progeny, as unfaithful expression of reporter genes in other cell types or even unintended labeling of the correct cell population at an undesired time point could lead to wrong conclusions. Here we report that all CreER(T2) mouse lines that we have studied exhibit a certain degree of Tamoxifen-independent, basal, Cre activity. Using Ai14 and Ai3, two commonly used fluorescent reporter genes, we show that those basal Cre activity levels are sufficient to label a significant amount of cells in a variety of tissues during embryogenesis, postnatal development and adulthood. This unintended labelling of cells imposes a serious problem for lineage tracing and mosaic analysis experiments. Importantly, however, we find that reporter constructs differ greatly in their susceptibility to basal CreER(T2) activity. While Ai14 and Ai3 easily recombine under basal CreER(T2) activity levels, mTmG and R26R-EYFP rarely become activated under these conditions and are therefore better suited for cell tracking experiments.

  • 2.
    Frye, Maike
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Taddei, Andrea
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Dierkes, Cathrin
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fielden, Matthew
    Albanova Univ Ctr, KTH Royal Inst Technol, Dept Appl Phys, S-10691 Stockholm, Sweden..
    Ortsäter, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Kazenwadel, Jan
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Calado, Dinis P.
    Francis Crick Inst, Immun & Canc Lab, 1 Midland Rd, London NW1 1AT, England..
    Ostergaard, Pia
    St Georges Univ London, Mol & Clin Sci Inst, Lymphovasc Res Unit, London SW17 0RE, England..
    Salminen, Marjo
    Univ Helsinki, Dept Vet Biosci, Helsinki 00014, Finland..
    He, Liqun
    Tianjin Med Univ, Gen Hosp, Minist Educ & Tianjin City, Tianjin Neurol Inst,Dept Neurosurg,Key Lab Post, Tianjin 300052, Peoples R China..
    Harvey, Natasha L.
    Univ South Australia, Ctr Canc Biol, Adelaide, SA 5000, Australia.;SA Pathol, Adelaide, SA 5000, Australia..
    Kiefer, Friedemann
    Max Planck Inst Mol Biomed, D-48149 Munster, Germany.;Univ Munster, EIMI, D-48149 Munster, Germany..
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed)
    Abstract [en]

    Tissue and vessel wall stiffening alters endothelial cell properties and contributes to vascular dysfunction. However, whether extracellular matrix (ECM) stiffness impacts vascular development is not known. Here we show that matrix stiffness controls lymphatic vascular morphogenesis. Atomic force microscopy measurements in mouse embryos reveal that venous lymphatic endothelial cell (LEC) progenitors experience a decrease in substrate stiffness upon migration out of the cardinal vein, which induces a GATA2-dependent transcriptional program required to form the first lymphatic vessels. Transcriptome analysis shows that LECs grown on a soft matrix exhibit increased GATA2 expression and a GATA2-dependent upregulation of genes involved in cell migration and lymphangiogenesis, including VEGFR3. Analyses of mouse models demonstrate a cell-autonomous function of GATA2 in regulating LEC responsiveness to VEGF-C and in controlling LEC migration and sprouting in vivo. Our study thus uncovers a mechanism by which ECM stiffness dictates the migratory behavior of LECs during early lymphatic development.

  • 3.
    Gardenier, Jason C.
    et al.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Hespe, Geoffrey E.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Kataru, Raghu P.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Savetsky, Ira L.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Torrisi, Jeremy S.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Nores, Gabriela D. Garcia
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Dayan, Joseph J.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Chang, David
    Univ Chicago Med & Biol Sci, Sect Plast & Reconstruct Surg, Chicago, IL USA..
    Zampell, Jamie
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid, Spain..
    Mehrara, Babak J.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema2016In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 15, article id e84095Article in journal (Refereed)
    Abstract [en]

    Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used Cre-lox mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4(+) cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.

  • 4.
    Gramolelli, Silvia
    et al.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Cheng, Jianpin
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vaha-Koskela, Markus
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Elbasani, Endrit
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Kaivanto, Elisa
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Rantanen, Ville
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Tuohinto, Krista
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Hautaniemi, Sampsa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Bower, Mark
    Chelsea & Westminster Hosp, London, England;Imperial Coll London, London, England.
    Haglund, Caj
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Univ Helsinki, Dept Surg, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland;Univ Helsinki, Dept Pathol, Helsinki, Finland.
    Alitalo, Kari
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Petrova, Tatiana V.
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Lehti, Kaisa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Ojala, Paivi M.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Imperial Coll London, Dept Med, Div Infect Dis, Sect Virol, London, England;Fdn Finnish Canc Inst, Helsinki, Finland.
    PROX1 is a transcriptional regulator of MMP142018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9531Article in journal (Refereed)
    Abstract [en]

    The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

  • 5.
    Gramolelli, Silvia
    et al.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Cheng, Jianpin
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Vaha-Koskela, Markus
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Elbasani, Endrit
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Kaivanto, Elisa
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Rantanen, Ville
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Tuohinto, Krista
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Hautaniemi, Sampsa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland.
    Bower, Mark
    Chelsea & Westminster Hosp, London, England;Imperial Coll London, London, England.
    Haglund, Caj
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Univ Helsinki, Dept Surg, Helsinki, Finland;Helsinki Univ Hosp, Helsinki, Finland;Univ Helsinki, Dept Pathol, Helsinki, Finland.
    Alitalo, Kari
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Petrova, Tatiana V.
    CHU Vaudois, Dept Oncol, Lausanne, Switzerland;Univ Lausanne, Lausanne, Switzerland;Ludwig Inst Canc Res, Lausanne, Switzerland.
    Lehti, Kaisa
    Univ Helsinki, Genome Scale Biol, Res Programs Unit, Helsinki, Finland;Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Ojala, Paivi M.
    Univ Helsinki, Translat Canc Biol, Res Programs Unit, Helsinki, Finland;Imperial Coll London, Dept Med, Div Infect Dis, Sect Virol, London, England;Fdn Finnish Canc Inst, Helsinki, Finland.
    PROX1 is a transcriptional regulator of MMP142018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9531Article in journal (Refereed)
    Abstract [en]

    The transcription factor PROX1 is essential for development and cell fate specification. Its function in cancer is context-dependent since PROX1 has been shown to play both oncogenic and tumour suppressive roles. Here, we show that PROX1 suppresses the transcription of MMP14, a metalloprotease involved in angiogenesis and cancer invasion, by binding and suppressing the activity of MMP14 promoter. Prox1 deletion in murine dermal lymphatic vessels in vivo and in human LECs increased MMP14 expression. In a hepatocellular carcinoma cell line expressing high endogenous levels of PROX1, its silencing increased both MMP14 expression and MMP14-dependent invasion in 3D. Moreover, PROX1 ectopic expression reduced the MMP14-dependent 3D invasiveness of breast cancer cells and angiogenic sprouting of blood endothelial cells in conjunction with MMP14 suppression. Our study uncovers a new transcriptional regulatory mechanism of cancer cell invasion and endothelial cell specification.

  • 6.
    Huang, Jung-Ju
    et al.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA.;Chang Gung Univ, Chang Gung Mem Hosp, Div Reconstruct Microsurg, Dept Plast & Reconstruct Surg, Taoyuan, Taiwan..
    Gardenier, Jason C.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Hespe, Geoffrey E.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Nores, Gabriela D. Garcia
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Kataru, Raghu P.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Ly, Catherine L.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr, Transgen Mice Unit, Biotechol Programme, Madrid, Spain..
    Mehrara, Babak J.
    Mem Sloan Kettering Canc Ctr, Dept Surg, Div Plast & Reconstruct Surg, 1275 York Ave, New York, NY 10021 USA..
    Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168259Article in journal (Refereed)
    Abstract [en]

    Introduction Secondary lymphedema is a common complication of cancer treatment and recent studies have demonstrated that lymph node transplantation (LNT) can decrease swelling, as well as the incidence of infections. However, although these results are exciting, the mechanisms by which LNT improves these pathologic findings of lymphedema remain unknown. Using a transgenic mouse model of lymphedema, this study sought to analyze the effect of LNT on lymphatic regeneration and T cell-mediated immune responses. Methods We used a mouse model in which the expression of the human diphtheria toxin receptor is driven by the FLT4 promoter to enable the local ablation of the lymphatic system through subdermal hindlimb diphtheria toxin injections. Popliteal lymph node dissection was subsequently performed after a two-week recovery period, followed by either orthotopic LNT or sham surgery after an additional two weeks. Hindlimb swelling, lymphatic vessel regeneration, immune cell trafficking, and T cell-mediated immune responses were analyzed 10 weeks later. Results LNT resulted in a marked decrease in hindlimb swelling, fibroadipose tissue deposition, and decreased accumulation of perilymphatic inflammatory cells, as compared to controls. In addition, LNT induced a marked lymphangiogenic response in both capillary and collecting lymphatic vessels. Interestingly, the resultant regenerated lymphatics were abnormal in appearance on lymphangiography, but LNT also led to a notable increase in dendritic cell trafficking from the periphery to the inguinal lymph nodes and improved adaptive immune responses. Conclusions LNT decreases pathological changes of lymphedema and was shown to potently induce lymphangiogenesis. Lymphatic vessels induced by LNT were abnormal in appearance, but were functional and able to transport antigen-presenting cells. Animals treated with LNT have an increased ability to mount T cell-mediated immune responses when sensitized to antigens in the affected hindlimb.

  • 7.
    Martinez-Corral, Ines
    et al.
    Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
    Mäkinen, Taija
    Lymphatic Development Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
    Regulation of lymphatic vascular morphogenesis: Implications for pathological (tumor) lymphangiogenesis2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 11, p. 1618-1625Article, review/survey (Refereed)
    Abstract [en]

    Lymphatic vasculature forms the second part of our circulatory system that plays a critical role in tissue fluid homeostasis. Failure of the lymphatic system can lead to excessive accumulation of fluid within the tissue, a condition called lymphedema. Lymphatic dysfunction has also been implicated in cancer metastasis as well as pathogenesis of obesity, atherosclerosis and cardiovascular disease. Since the identification of the first lymphatic marker VEGFR-3 and growth factor VEGF-C almost 20 years ago, a great progress has been made in understanding the mechanisms of lymphangiogenesis. This has been achieved largely through characterization of animal models with specific lymphatic defects and identification of genes causative of human hereditary lymphedema syndromes. In this review we will summarize the current understanding of the regulation of lymphatic vascular morphogenesis, focusing on mechanisms that have been implicated in both developmental and pathological (tumor) lymphangiogenesis.

  • 8.
    Martinez-Corral, Ines
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Frye, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Diegez-Hurtado, Rodrigo
    Olmeda, David
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system2016In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 19, no 3, p. 433-445Article in journal (Refereed)
    Abstract [en]

    The lymphatic system is essential in many physiological and pathological processes. Still, much remains to be known about the molecular mechanisms that control its development and function and how to modulate them therapeutically. The study of these mechanisms will benefit from better controlled genetic mouse models targeting specifically lymphatic endothelial cells. Among the genes expressed predominantly in lymphatic endothelium, Vegfr3 was the first one identified and is still considered to be one of the best lymphatic markers and a key regulator of the lymphatic system. Here, we report the generation of a Vegfr3-CreER (T2) knockin mouse by gene targeting in embryonic stem cells. This mouse expresses the tamoxifen-inducible CreER(T2) recombinase under the endogenous transcriptional control of the Vegfr3 gene without altering its physiological expression or regulation. The Vegfr3-CreER (T2) allele drives efficient recombination of floxed sequences upon tamoxifen administration specifically in Vegfr3-expressing cells, both in vitro, in primary lymphatic endothelial cells, and in vivo, at different stages of mouse embryonic development and postnatal life. Thus, our Vegfr3-CreER (T2) mouse constitutes a new powerful genetic tool for lineage tracing analysis and for conditional gene manipulation in the lymphatic endothelium that will contribute to improve our current understanding of this system.

  • 9.
    Martinez-Corral, Ines
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Tatin, Florence
    Kizhatil, Krishnakumar
    John, Simon W. M.
    Alitalo, Kari
    Ortega, Sagrario
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Nonvenous Origin of Dermal Lymphatic Vasculature2015In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 10, p. 1649-1654Article in journal (Refereed)
    Abstract [en]

    Rationale: The formation of the blood vasculature is achieved via 2 fundamentally different mechanisms, de novo formation of vessels from endothelial progenitors (vasculogenesis) and sprouting of vessels from pre-existing ones (angiogenesis). In contrast, mammalian lymphatic vasculature is thought to form exclusively by sprouting from embryonic veins (lymphangiogenesis). Alternative nonvenous sources of lymphatic endothelial cells have been suggested in chicken and Xenopus, but it is unclear whether they exist in mammals. Objective: We aimed to clarify the origin of the murine dermal lymphatic vasculature. Methods and Results: We performed lineage tracing experiments and analyzed mutants lacking the Prox1 transcription factor, a master regulator of lymphatic endothelial cell identity, in Tie2 lineage venous-derived lymphatic endothelial cells. We show that, contrary to current dogma, a significant part of the dermal lymphatic vasculature forms independently of sprouting from veins. Although lymphatic vessels of cervical and thoracic skin develop via sprouting from venous-derived lymph sacs, vessels of lumbar and dorsal midline skin form via assembly of non-Tie2-lineage cells into clusters and vessels through a process defined as lymphvasculogenesis. Conclusions: Our results demonstrate a significant contribution of nonvenous-derived cells to the dermal lymphatic vasculature. Demonstration of a previously unknown lymphatic endothelial cell progenitor population will now allow further characterization of their origin, identity, and functions during normal lymphatic development and in pathology, as well as their potential therapeutic use for lymphatic regeneration.

  • 10.
    Olmeda, David
    et al.
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Cerezo-Wallis, Daniela
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Riveiro-Falkenbach, Erica
    Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain..
    Pennacchi, Paula C.
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Contreras-Alcalde, Marta
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Ibarz, Nuria
    Spanish Natl Canc Res Ctr CNIO, Prote Unit, Biotechnol Programme, Madrid 28029, Spain..
    Cifdaloz, Metehan
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.;Roche Innovat Ctr Munich, Roche Pharma Res & Early Dev, D-82377 Penzberg, Germany..
    Catena, Xavier
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Calvo, Tonantzin G.
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Canon, Estela
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Alonso-Curbelo, Direna
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain.;Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Suarez, Javier
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Osterloh, Lisa
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Grana, Osvaldo
    Spanish Natl Canc Res Ctr CNIO, Bioinformat Unit, Struct Biol & Biocomp Programme, Madrid 28029, Spain..
    Mulero, Francisca
    Spanish Natl Canc Res Ctr CNIO, Mol Imaging Unit, Biotechnol Programme, Madrid 28029, Spain..
    Megias, Diego
    Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Biotechnol Programme, Madrid 28029, Spain..
    Canamero, Marta
    Spanish Natl Canc Res Ctr CNIO, Histopathol Unit, Biotechnol Programme, Madrid 28029, Spain..
    Martinez-Torrecuadrada, Jorge L.
    Spanish Natl Canc Res Ctr CNIO, Crystallog & Prot Engn Unit, Biotechnol Programme, Madrid 28029, Spain..
    Mondal, Chandrani
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA..
    Di Martino, Julie
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA..
    Lora, David
    Hosp Univ 12 Octubre, Inst I 12, CIBERESP, Madrid 28041, Spain..
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid 28029, Spain.
    Bravo-Cordero, J. Javier
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, Div Hematol & Oncol, Dept Med, New York, NY 10029 USA..
    Munoz, Javier
    Spanish Natl Canc Res Ctr CNIO, Prote Unit, Biotechnol Programme, Madrid 28029, Spain..
    Puig, Susana
    Hosp Clin Barcelona, Inst Invest Biomed August Pi & Sunyer, Melanoma Unit, Dermatol Dept, E-08036 Barcelona, Spain..
    Ortiz-Romero, Pablo
    Univ Complutense Madrid, Hosp Univ Octubre 12, Inst I 12, Dept Dermatol,Med Sch, Madrid 28041, Spain..
    Rodriguez-Peralto, Jose L.
    Univ Complutense Madrid, Inst I 12, Hosp Univ Octubre 12, Med Sch,Dept Pathol, Madrid 28041, Spain..
    Ortega, Sagrario
    Spanish Natl Canc Res Ctr CNIO, Transgen Mice Unit, Biotechnol Programme, Madrid 28029, Spain..
    Soengas, Maria S.
    Spanish Natl Canc Res Ctr CNIO, Melanoma Lab, Mol Oncol Programme, Madrid 28029, Spain..
    Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine2017In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 546, no 7660, p. 676-680Article in journal (Refereed)
    Abstract [en]

    Cutaneous melanoma is a type of cancer with an inherent potential for lymph node colonization, which is generally preceded by neolymphangiogenesis(1-3). However, sentinel lymph node removal does not necessarily extend the overall survival of patients with melanoma(4,5). Moreover, lymphatic vessels collapse and become dysfunctional as melanomas progress(6,7). Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumours and/or their stroma have been proposed to condition pre-metastatic sites in patients with melanoma(8-14). Still, the identities and prognostic value of lymphangiogenic mediators remain unclear(2,14). Moreover, our understanding of lymphangiogenesis (in melanomas and other tumour types) is limited by the paucity of mouse models for live imaging of distal pre-metastatic niches(15). Injectable lymphatic tracers have been developed(7), but their limited diffusion precludes whole-body imaging at visceral sites(16). Vascular endothelial growth factor receptor 3 (VEGFR3) is an attractive 'lymphoreporter' 17 because its expression is strongly downregulated in normal adult lymphatic endothelial cells, but is activated in pathological situations such as inflammation and cancer(17,18). Here, we exploit this inducibility of VEGFR3 to engineer mouse melanoma models for whole-body imaging of metastasis generated by human cells, clinical biopsies or endogenously deregulated oncogenic pathways. This strategy revealed early induction of distal pre-metastatic niches uncoupled from lymphangiogenesis at primary lesions. Analyses of the melanoma secretome and validation in clinical specimens showed that the heparin-binding factor midkine is a systemic inducer of neo-lymphangiogenesis that defines patient prognosis. This role of midkine was linked to a paracrine activation of the mTOR pathway in lymphatic endothelial cells. These data support the use of VEGFR3 reporter mice as a 'MetAlert' discovery platform for drivers and inhibitors of metastasis.

  • 11.
    Pujol, Francoise
    et al.
    I2MC INSERM UMR 1048, Toulouse, France.
    Hodgson, Tina
    Kings Coll London, Dept Craniofacial Dev & Stem Cell Biol, London, England.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Prats, Anne-Catherine
    I2MC INSERM UMR 1048, Toulouse, France.
    Devenport, Danelle
    Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA.
    Takeichi, Masatoshi
    RIKEN Ctr Dev Biol, Lab Cell Adhes & Tissue Patterning, Kobe, Hyogo, Japan.
    Genot, Elisabeth
    Univ Bordeaux, INSERM, Bordeaux, France.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Francis-West, Philippa
    Kings Coll London, Dept Craniofacial Dev & Stem Cell Biol, London, England.
    Garmy-Susini, Barbara
    I2MC INSERM UMR 1048, Toulouse, France.
    Tatin, Florence
    I2MC INSERM UMR 1048, Toulouse, France.
    Dachsousl-Fat4 Signaling Controls Endothelial Cell Polarization During Lymphatic Valve Morphogenesis-Brief Report2017In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 37, no 9, p. 1732-1735Article in journal (Refereed)
    Abstract [en]

    Objective-The purpose of this study was to investigate the role of Fat4 and Dachsous 1 signaling in the lymphatic vasculature. Approach and Results-Phenotypic analysis of the lymphatic vasculature was performed in mice lacking functional Fat4 or Dachsousl. The overall architecture of lymphatic vasculature is unaltered, yet both genes are specifically required for lymphatic valve morphogenesis. Valve endothelial cells (Proxl(high) [prospero homeobox protein 1] cells) are disoriented and failed to form proper valve leaflets. Using Lifeact-GFP (green fluorescent protein) mice, we revealed that valve endothelial cells display prominent actin polymerization. Finally, we showed the polarized recruitment of Dachsousl to membrane protrusions and cellular junctions of valve endothelial cells in vivo and in vitro. Conclusions-Our data demonstrate that Fat4 and Dachsousl are critical regulators of valve morphogenesis. This study highlights that valve defects may contribute to lymphedema in Hennekam syndrome caused by Fat4 mutations.

  • 12.
    Stanczuk, Lukas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Fruttiger, Marcus
    Adams, Ralf H.
    Saur, Dieter
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Ortega, Sagrario
    Alitalo, Kari
    Graupera, Mariona
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels2015In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed)
    Abstract [en]

    Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.

  • 13.
    Ulvmar, Maria H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins2016In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 54, no 6, p. 350-358Article in journal (Refereed)
    Abstract [en]

    The Pdgfrb-Cre line has been used as a tool to specifically target pericytes and vascular smooth muscle cells. Recent studies showed additional targeting of cardiac and mesenteric lymphatic endothelial cells (LECs) by the Pdgfrb-Cre transgene. In the heart, this was suggested to provide evidence for a previously unknown non-venous source of LECs originating from yolk sac (YS) hemogenic endothelium (HemEC). Here we show that Pdgfrb-Cre does not, however, target YS HemEC or YS-derived erythro-myeloid progenitors (EMPs). Instead, a high proportion of ECs in embryonic blood vessels of multiple organs, as well as venous derived LECs were targeted. Assessment of temporal Cre activity using the R26-mTmG double reporter suggested recent occurrence of Pdgfrb-Cre recombination in both blood and lymphatic ECs. It thus cannot be excluded that Pdgfrb-Cre mediated targeting of LECs is due to de novo expression of the Pdgfrb-Cre transgene or their previously established venous endothelial origin. Importantly, Pdgfrb-Cre targeting of LECs does not provide evidence for YS HemEC origin of the lymphatic vasculature. Our results highlight the need for careful interpretation of lineage tracing using constitutive Cre lines that cannot discriminate active from historical expression. The early vascular targeting by the Pdgfrb-Cre also warrants consideration for its use in studies of mural cells.

  • 14.
    Zhang, Yan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ulvmar, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stanczuk, Lukas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Frye, Maike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alitalo, Kari
    Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, FIN-00014, Helsinki, Finland.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms2018In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed)
    Abstract [en]

    Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3-LECs non-cell-autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth.

  • 15.
    Zhang, Yang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Stritt, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Martinez-Corral, Ines
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Laviña, Bàrbara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mäkinen, Taija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Alternative lymphatic endothelial progenitor cells compensate for the loss of non-venous-derived progenitors to form mesenteric lymphatic vesselsManuscript (preprint) (Other academic)
1 - 15 of 15
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