We study the fundamental mechanisms that govern the development, maintenance, and regeneration of a functional lymphatic vasculature. Additionally, we investigate the involvement 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 plays an increasingly recognized role as a multifaceted regulator of tissue homeostasis and regeneration. Traditionally, its primary function involves draining fluid, macromolecules, and immune cells from peripheral tissues to 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 their production of paracrine (lymphangiocrine) factors that regulate organ growth and regeneration. The growing recognition 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. 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.
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). 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. 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.
Schnabellehner S, Kraft M, Schoofs H, Ortsäter H, Mäkinen T. Penile cavernous sinusoids are Prox1-positive hybrid vessels. Vasc Biol Dec 1:VB-23-0014. doi: 10.1530/VB-23-0014 (2024).
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).
Zhang Y, Ortsäter H, Martinez-Corral I, Mäkinen T. Cdh5-lineage independent origin of dermal lymphatics shown by temporally restricted lineage tracing. Life Sci Alliance 5(11):e202201561. doi: 10.26508/lsa.202201561 (2022).
Ortsäter H, Hernández Vásquez MN, Ulvmar MH, Gow A, Mäkinen T. An inducible Cldn11-CreERT2 mouse line for selective targeting of lymphatic valves. Genesis Aug 2:e23439. doi: 10.1002/dvg.23439 (2021).
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).
Zhang Y, Daubel N, Stritt S, Mäkinen T. Transient loss of venous integrity during developmental vascular remodeling leads to red blood cell extravasation and clearance by lymphatic vessels. Development 145: pii:dev156745 doi: 10.1242/dev.156745 (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-9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 17:175-186 (2009).