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Martinez-Corral, Ines
Publications (10 of 10) Show all publications
Zhang, Y., Ulvmar, M. H., Stanczuk, L., Martinez-Corral, I., Frye, M., Alitalo, K. & Mäkinen, T. (2018). Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nature Communications, 9(1), Article ID 1296.
Open this publication in new window or tab >>Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, no 1, article id 1296Article in journal (Refereed) Published
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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-348896 (URN)10.1038/s41467-018-03692-0 (DOI)000429003400001 ()29615616 (PubMedID)
Funder
Swedish Research Council, 542-2014-3535EU, European Research Council, ERC-2014-CoG-646849Knut and Alice Wallenberg Foundation, 2015.0030Stiftelsen G A Johanssons Minnesfond
Available from: 2018-04-18 Created: 2018-04-18 Last updated: 2018-06-13Bibliographically approved
Frye, M., Taddei, A., Dierkes, C., Martinez-Corral, I., Fielden, M., Ortsäter, H., . . . Mäkinen, T. (2018). Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nature Communications, 9, Article ID 1511.
Open this publication in new window or tab >>Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 1511Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-352466 (URN)10.1038/s41467-018-03959-6 (DOI)000430196200006 ()29666442 (PubMedID)
Funder
Swedish Research Council, D0368601]Swedish Research Council, 542-2014-3535]Swedish Cancer Society, CAN 2013/387EU, European Research Council, ERC-2014-CoG-646849Wellcome trust, FC001057
Available from: 2018-06-07 Created: 2018-06-07 Last updated: 2018-06-07Bibliographically approved
Olmeda, D., Cerezo-Wallis, D., Riveiro-Falkenbach, E., Pennacchi, P. C., Contreras-Alcalde, M., Ibarz, N., . . . Soengas, M. S. (2017). Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine. Nature, 546(7660), 676-680
Open this publication in new window or tab >>Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine
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2017 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 546, no 7660, p. 676-680Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-329632 (URN)10.1038/nature22977 (DOI)000404332000052 ()28658220 (PubMedID)
Available from: 2017-09-26 Created: 2017-09-26 Last updated: 2017-09-26Bibliographically approved
Gardenier, J. C., Hespe, G. E., Kataru, R. P., Savetsky, I. L., Torrisi, J. S., Nores, G. D. G., . . . Mehrara, B. J. (2016). Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema. JCI INSIGHT, 1(15), Article ID e84095.
Open this publication in new window or tab >>Diphtheria toxin-mediated ablation of lymphatic endothelial cells results in progressive lymphedema
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2016 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 1, no 15, article id e84095Article in journal (Refereed) Published
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.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-310029 (URN)10.1172/jci.insight.84095 (DOI)000387123200001 ()27699240 (PubMedID)
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
Huang, J.-J., Gardenier, J. C., Hespe, G. E., Nores, G. D. G., Kataru, R. P., Ly, C. L., . . . Mehrara, B. J. (2016). Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema. PLoS ONE, 11(12), Article ID e0168259.
Open this publication in new window or tab >>Lymph Node Transplantation Decreases Swelling and Restores Immune Responses in a Transgenic Model of Lymphedema
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168259Article in journal (Refereed) Published
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.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-316432 (URN)10.1371/journal.pone.0168259 (DOI)000392745600059 ()27942023 (PubMedID)
Funder
NIH (National Institute of Health), R01 HL111130-01 R21-CA194882 T32 CA9501-27 T32 CA9501-29
Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-11-29Bibliographically approved
Ulvmar, M. H., Martinez-Corral, I., Stanczuk, L. & Mäkinen, T. (2016). Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins. Genesis, 54(6), 350-358
Open this publication in new window or tab >>Pdgfrb-Cre targets lymphatic endothelial cells of both venous and non-venous origins
2016 (English)In: Genesis, ISSN 1526-954X, E-ISSN 1526-968X, Vol. 54, no 6, p. 350-358Article in journal (Refereed) Published
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.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-288517 (URN)10.1002/dvg.22939 (DOI)000379165300004 ()27060598 (PubMedID)
External cooperation:
Funder
EU, European Research Council, ERC-2014-CoG-646849Swedish Research Council
Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2018-01-10Bibliographically approved
Martinez-Corral, I., Stanczuk, L., Frye, M., Ulvmar, M. H., Diegez-Hurtado, R., Olmeda, D., . . . Ortega, S. (2016). Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system. Angiogenesis, 19(3), 433-445
Open this publication in new window or tab >>Vegfr3-CreER (T2) mouse, a new genetic tool for targeting the lymphatic system
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2016 (English)In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 19, no 3, p. 433-445Article in journal (Refereed) Published
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.

National Category
Cardiac and Cardiovascular Systems
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-288518 (URN)10.1007/s10456-016-9505-x (DOI)000379219600013 ()26993803 (PubMedID)
Funder
Swedish Research CouncilEU, European Research Council, ERC-2014-CoG 646849
Note

Erratum in: Angiogenesis 19(3) p. 447 DOI: 10.1007/s10456-016-9518-5

Available from: 2016-04-28 Created: 2016-04-28 Last updated: 2017-11-30Bibliographically approved
Stanczuk, L., Martinez-Corral, I., Ulvmar, M. H., Zhang, Y., Laviña, B., Fruttiger, M., . . . Mäkinen, T. (2015). cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels. Cell reports, 10(10), 1708-1721
Open this publication in new window or tab >>cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
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2015 (English)In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 10, no 10, p. 1708-1721Article in journal (Refereed) Published
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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-251417 (URN)10.1016/j.celrep.2015.02.026 (DOI)000351316700008 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-04-25Bibliographically approved
Martinez-Corral, I., Ulvmar, M. H., Stanczuk, L., Tatin, F., Kizhatil, K., John, S. W. M., . . . Mäkinen, T. (2015). Nonvenous Origin of Dermal Lymphatic Vasculature. Circulation Research, 116(10), 1649-1654
Open this publication in new window or tab >>Nonvenous Origin of Dermal Lymphatic Vasculature
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2015 (English)In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 116, no 10, p. 1649-1654Article in journal (Refereed) Published
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.

Keywords
developmental biology, endothelial cells, endothelial progenitor cells, lymphangiogenesis, lymphatic vessels
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-255071 (URN)10.1161/CIRCRESAHA.116.306170 (DOI)000354061300011 ()25737499 (PubMedID)
Funder
Swedish Research Council
Available from: 2015-06-22 Created: 2015-06-12 Last updated: 2017-12-04
Martinez-Corral, I. & Mäkinen, T. (2013). Regulation of lymphatic vascular morphogenesis: Implications for pathological (tumor) lymphangiogenesis. Experimental Cell Research, 319(11), 1618-1625
Open this publication in new window or tab >>Regulation of lymphatic vascular morphogenesis: Implications for pathological (tumor) lymphangiogenesis
2013 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 11, p. 1618-1625Article, review/survey (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220658 (URN)10.1016/j.yexcr.2013.01.016 (DOI)23395992 (PubMedID)
Available from: 2014-03-18 Created: 2014-03-18 Last updated: 2017-12-05Bibliographically approved
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