We study the fundamental mechanisms that govern the development, maintenance, and regeneration of a functional lymphatic vasculature. Additionally, we investigate the role of lymphatic vessels in organ-specific physiology and disease processes.
Taija Mäkinen
DIRECTOR, GROUP LEADER
PROFESSOR
CONTACT
TAIJA.MAKINEN@HELSINKI.FI
+46 70 4250360
The lymphatic vasculature is increasingly recognized for its role as a multifaceted regulator of tissue homeostasis and regeneration. Traditionally, its primary function has been to drain fluid, macromolecules, and immune cells from peripheral tissues into the systemic circulation via lymph nodes. Dysfunction of lymphatic vessels can lead to the accumulation of protein-rich fluid in tissues, known as lymphedema, and impaired immune responses.
Recent findings have revealed additional roles of the lymphatic system, including active modulation of adaptive immunity by lymphatic endothelial cells (LECs) and the secretion of paracrine (lymphangiocrine) factors that regulate organ growth and regeneration. The expanding understanding of the diverse functions of the lymphatic system in essential physiological processes and disease conditions, such as autoimmune disease and atherosclerosis, underscores the need for a better understanding of the underlying mechanisms.
Our research seeks to comprehensively explore the fundamental mechanisms that regulate the lymphatic vasculature and its role in organ-specific physiology and disease processes. This knowledge is critical for understanding pathological alterations in lymphatic vessels that contribute to the onset and progression of diseases, providing opportunities for the development of novel therapies.
The lymphatic system comprises a hierarchical network of vessels, each with distinct functions: lymphatic capillaries absorb interstitial fluid, while collecting lymphatic vessels transport lymph to the cardiovascular system. Our group has made significant contributions to uncovering the molecular and cellular mechanisms underlying the functional specialization of lymphatic vasculature during normal development. In addition, our studies on early embryonic vessel formation led to the discovery of an unexpected organ-specific mechanism of lymphatic morphogenesis that we termed lymphvasculogenesis and involves a novel origin of lymphatic vessels (Martinez-Corral et al, Circ Res 2015; Stanczuk et al, Cell Rep 2015). Our findings not only challenged the previously accepted notion of the sole venous origin of lymphatic vasculature, but they also identified a novel progenitor population with potential therapeutic implications for restoring lymphatic function.
Our current research seeks to elucidate paracrine, tissue-specific, and vessel-specific mechanisms governing lymphatic vessel growth and regeneration that may provide targets for treating diseases associated with lymphatic vessel dysfunction.
LECs as paracrine regulators of tissue homeostasis, regeneration and disease. Lymphatic vessels across different organs not only originate from diverse developmental sources but also rely on different growth factor signalling pathways and exhibit remarkable tissue-specific specialisation and involvement in disease. Recent advancements in single-cell transcriptomics have shed light on the heterogeneity of LECs, revealing distinct molecular identities of LEC subtypes across different tissues and vessel types. Our analysis of LECs isolated from mouse skin identified a previously unknown subpopulation of LECs in capillary terminals, termed immune-interacting LECs (iLECs) (Petkova et al, JEM 2023). Intriguingly, we observed selective expansion of the iLEC population in a genetic mouse model of lymphatic malformation (LM), characterized by uncontrolled vessel growth due to an activating mutation in the Pik3ca gene. Our findings further revealed that iLECs play a pivotal role in driving disease pathology by secreting factors that promote macrophage recruitment. In turn, macrophages produce pro-lymphangiogenic vascular endothelial growth factor C (VEGF-C), thereby exacerbating LM progression (Martinez-Corral et al, Nat Commun 2020; Petkova et al, JEM 2023). This close interplay between LECs and immune cells in LM has led us to further investigate the paracrine functions of LECs as potential organ-specific regulators of developmental and pathological processes in other contexts.
Vascular resilience mechanisms. Beyond characterizing the molecular identities of endothelial cells across different organs, a key focus of our research is to understand how individual cells and vessels behave in vivo, providing deeper insight into both physiological and pathological conditions. To achieve this, we have developed advanced imaging methodologies that, for the first time, enable high-resolution visualization of individual endothelial cells, their morphology, and movements in living animals. This approach led to the discovery that dynamic cytoskeletal regulation of the distinctive oak leaf-like shape of capillary LECs plays a critical role in maintaining vessel integrity under homeostasis (Schoofs et al, Nature in press). Our ongoing research aims to further elucidate the mechanisms that preserve vessel integrity while maintaining permeable cell-cell contacts that support interstitial fluid uptake.
Gauri Arolkar, PhD student
Vishal Mohanakrishnan, postdoc
Yan Zhang, researcher
Yizhou Hu, researcher/bioinformatician
Uppsala
Bojana Jakic, postdoc
Charlotte Rorsman, senior technician
Filipa Oliveira, PhD student
Ingvar Ferby, researcher
Sarah Schnabellehner, postdoc
Sofie Lunell Segerqvist, laboratory assistant
Zuzana Varaliova, postdoc
Full list
https://www.webofscience.com/wos/author/record/C-5765-2014
Selected
Schoofs H, Daubel N, Schnabellehner S, Grönloh MLB, Palacios Martínez S, Halme A, Marks AM, Jeansson M, Barcos S, Brakebusch C, Benedito R, Engelhardt B, Vestweber D, Gängel K, Linsenmeier F, Schürmann S, Saharinen P, van Buul JD, Friedrich O, Smith RS, Majda M, Mäkinen T. Dynamic cytoskeletal regulation of cell shape supports resilience of lymphatic endothelium. Nature in press (2025).
Petkova M, Kraft M, Stritt S, Martinez-Corral I, Ortsäter H, Vanlandewijck M, Jakic B, Baselga E, Castillo SD, Graupera M, Betsholtz C, Mäkinen T. Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation. J Exp Med Apr 3;220(4):e20220741. doi: 10.1084/jem.20220741 (2023).
Hernández Vásquez MN, Ulvmar MH, González-Loyola A, Kritikos I, Sun Y, He L, Halin C, Petrova TV, Mäkinen T. Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels. EMBO J 40(12):e107192. doi: 10.15252/embj.2020107192 (2021).
Frye M, Stritt S, Ortsäter H, Hernandez-Vasquez M, Kaakinen M, Vicente A, Wiseman J, Eklund L, Martinez-Torrecuadrada JL, Vestweber D, Mäkinen T. EphrinB2-EPHB4 signalling provides Rho-mediated homeostatic control of lymphatic endothelial cell junction integrity. eLife 9:e57732 (2020).
Martinez-Corral I, Zhang Y, Petkova M, Ortsäter H, Sjöberg S, Diez SC, Brouillard P, Libbrecht L, Graupera M, Alitalo K, Boon L, Vikkula M, Mäkinen T. Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation. Nat Commun 11:2869 doi: 10.1038/s41467-020-16496-y (2020).
Frye M, Taddei A, Dierkes C, Martinez-Corral I, Fielden M, Ortsäter H, Kazenwadel J, Calado DP, Ostergaard P, Salminen M, He L, Harvey N, Kiefer F, Mäkinen T. Matrix stiffness controls lymphatic vessel formation through regulation of a GATA2-dependent transcriptional program. Nat Commun, 9:1511 doi: 10.1038/s41467-018-03959-6 (2018).
Zhang Y, Ulvmar MH, Stanczuk L, Martinez-Corral I, Frye M, Alitalo, K, Mäkinen T. Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell-autonomous and non-cell-autonomous mechanisms. Nat Commun 9:1296 doi: 10.1038/s41467-018-03692-0 (2018).
Martinez-Corral I, Ulvmar MH, Stanczuk L, Tatin F, Kizhatil K, John SWM, Alitalo K, Ortega S, Makinen T. Non-venous origin of dermal lymphatic vasculature. Circ Res 116:1649-1654 (2015).
Stanczuk L, Martinez-Corral I, Ulvmar MH, Zhang Y, Lavina B, Fruttiger M, Adams RH, Saur D, Betsholtz C, Ortega S, Alitalo K, Graupera M, Mäkinen T. cKit lineage hemogenic endothelium-derived cells contribute to mesenteric lymphatic vessels. Cell Rep 10:1708-1721 (2015).
Tatin F, Taddei A, Weston A, Fuchs E, Devenport D, Tissir F, Makinen T. Planar cell polarity protein Celsr1 regulates endothelial adherens junctions and directed cell rearrangements during lymphatic valve morphogenesis. Dev Cell 15:31-44 (2013).
Lutter S, Xie S, Tatin F, Makinen T. Smooth muscle-endothelial cell communication activates Reelin signaling and regulates lymphatic vessel formation. J Cell Biol 197:837-49 (2012).
Bazigou E, Lyons OTA, Smith A, Venn GE, Cope C, Brown NA, Makinen T. Genes regulating lymphangiogenesis control venous valve formation and maintenance in mice. J Clin Invest 121:2984-92 (2011).
Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro A, Sheppard D, Makinen T. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 17:175-186 (2009).