Lars Jakobsson Group
Vascular morphogenesis and function in health and disease
Molecular and multi-cellular dynamics
Dysfunction and mispatterning of the blood and lymphatic vasculature are central in the progression or development of several diseases such as cancer, lymphedema, diabetic retinopathy, trauma, stroke complications, hereditary haemorrhagic telangiectasia (HHT) and ischemic heart disease.
The formation and function of the vasculature depend on the interplay between its major units; the endothelial cells (ECs), the supportive mural cells (pericytes and smooth muscle cells), and their shared basement membrane (BM).
We study the molecular and cellular processes whereby the blood vasculature adapts its size, architecture and function to optimally meet the changing demands from tissue with the aim to understand and prevent malformation and malfunction in disease.
We have previously revealed and described extensive cellular dynamics during blood vessel formation (angiogenesis) (Jakobsson et al, Nat Cell Biol, 2010).
Technology and resources
- We utilise mice with inducible and cell specific genetic gain- and loss- of function in combination with a repertoire of conditional and cell specific reporters allowing for lineage tracing, clonal analysis and cell sorting.
- Multi-photon intravital imaging
- Confocal live cell imaging
- Tissue-clearing techniques
- Light-sheet microscopy
- Large scale proteomics
- Mouse embryonic stem cell models
Multi-cellular interplay in regulation of vascular patterning and function
The interaction of mural and endothelial cells is known to be required for proper vascular function. We are currently characterizing this cellular interplay and its impact on vascular remodelling and function in various genetic models by live imaging techniques, ex vivo and in vivo.
Mechanisms of vascular malformation
The endothelial specific TGFß/BMP co-receptor Endoglin is required for vascular development and function. Mutations in this gene cause the human disease HHT, also known as the Osler Weber Rendu syndrome, characterised by vascular abnormalities and ruptures. We are currently studying the precise mechanisms and roles of Endoglin in development and function of the vasculature of the Central Nervous System (CNS). Our disease models, including genetic GOF, LOF and conditional reporters, provide unique information on vascular malformation. We are now investigating new targets to treat HHT1.
The Basement membrane – facilitating structured signalling
Endothelial cells and pericytes rest on a matrix of several proteins that interconnect to form the basement membrane (BM). Laminins are key components in the formation of the vascular BM. Alterations in the BM composition is commonly seen in tumours. Using conditional alleles we study the role of Laminins on vascular function, tumour growth and metastasis.
The lymphatic vasculature
In vivo imaging of cellular dynamics in vascular morphogenesis
We utilise in vivo, single and multiphoton confocal imaging of several organs (eye, ear and Cremaster) to describe the dynamics of vascular morphogenesis, permeability and function.
Loss of Endothelial Endoglin Promotes High-Output Heart Failure Through Peripheral Arteriovenous Shunting Driven by VEGF Signalling.
Tual-Chalot S, Garcia-Collado M, Redgrave RE, Singh E, Davison B, Park C, et al
Circ. Res. 2019 Dec;():
Characterization of multi-cellular dynamics of angiogenesis and vascular remodelling by intravital imaging of the wounded mouse cornea.
Wang Y, Jin Y, Laviña B, Jakobsson L
Sci Rep 2018 Jul;8(1):10672
Smooth muscle cell recruitment to lymphatic vessels requires PDGFB and impacts vessel size but not identity.
Wang Y, Jin Y, Mäe MA, Zhang Y, Ortsäter H, Betsholtz C, et al
Development 2017 10;144(19):3590-3601
Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling.
Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, et al
Nat. Cell Biol. 2017 Jun;19(6):639-652
Read the whole article.
Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues.
Sugden WW, Meissner R, Aegerter-Wilmsen T, Tsaryk R, Leonard EV, Bussmann J, et al
Nat. Cell Biol. 2017 Jun;19(6):653-665
Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRβ signaling.
Muhl L, Folestad EB, Gladh H, Wang Y, Moessinger C, Jakobsson L, et al
J. Cell. Sci. 2017 04;130(8):1365-1378
RhoA inhibits neural differentiation in murine stem cells through multiple mechanisms.
Yang J, Wu C, Stefanescu I, Jakobsson L, Chervoneva I, Horowitz A
Sci Signal 2016 07;9(438):ra76
TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis.
Pang M, Georgoudaki A, Lambut L, Johansson J, Tabor V, Hagikura K, et al
Oncogene 2016 Feb;35(6):748-60
Transforming growth factor β family members in regulation of vascular function: in the light of vascular conditional knockouts.
Jakobsson L, van Meeteren L
Exp. Cell Res. 2013 May;319(9):1264-70
The sphingosine-1-phosphate receptor S1PR1 restricts sprouting angiogenesis by regulating the interplay between VE-cadherin and VEGFR2.
Gaengel K, Niaudet C, Hagikura K, Laviña B, Siemsen B, Muhl L, et al
Dev. Cell 2012 Sep;23(3):587-99
The dynamics of developmental and tumor angiogenesis-a comparison.
Jin Y, Jakobsson L
Cancers (Basel) 2012 Apr;4(2):400-19
VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.
Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D, et al
Nat. Cell Biol. 2011 Sep;13(10):1202-13
Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting.
Jakobsson L, Franco C, Bentley K, Collins R, Ponsioen B, Aspalter I, et al
Nat. Cell Biol. 2010 Oct;12(10):943-53
Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization.
Kawamura H, Li X, Goishi K, van Meeteren LA, Jakobsson L, Cébe-Suarez S, et al
Blood 2008 Nov;112(9):3638-49
Laminin deposition is dispensable for vasculogenesis but regulates blood vessel diameter independent of flow.
Jakobsson L, Domogatskaya A, Tryggvason K, Edgar D, Claesson-Welsh L
FASEB J. 2008 May;22(5):1530-9
Endothelial cell migration in stable gradients of vascular endothelial growth factor A and fibroblast growth factor 2: effects on chemotaxis and chemokinesis.
Barkefors I, Le Jan S, Jakobsson L, Hejll E, Carlson G, Johansson H, et al
J. Biol. Chem. 2008 May;283(20):13905-12
Building blood vessels--stem cell models in vascular biology.
Jakobsson L, Kreuger J, Claesson-Welsh L
J. Cell Biol. 2007 Jun;177(5):751-5
Angiomotin regulates endothelial cell migration during embryonic angiogenesis.
Aase K, Ernkvist M, Ebarasi L, Jakobsson L, Majumdar A, Yi C, et al
Genes Dev. 2007 Aug;21(16):2055-68
Heparan sulfate in trans potentiates VEGFR-mediated angiogenesis.
Jakobsson L, Kreuger J, Holmborn K, Lundin L, Eriksson I, Kjellén L, et al
Dev. Cell 2006 May;10(5):625-34
The lab is part of V.A. Cure - a European MSCA-ITN network.
We are very grateful for the financial support from:
- The Cardiovascular Programme (KI and the Stockholm County Council)
- The European Commission
- Jeanssons Stiftelse
- Karolinska Institutet
- Magnus Bergvalls stiftelser
- Petrus och Augusta Hedlunds Stiftelse
- Ruth och Nils-Erik Stenbäcks stiftelse
- The Brain Foundation
- The Heart and Lung Foundation
- The Strategic Programme for Neuroscience, (Stratneuro, KI)
- The Swedish Cancer Society (Cancerfonden)
- The Swedish Medical Society
- The Swedish Research Council (Vetenskapsrådet)
- William K. Bowes, Jr. Foundation
- Åke Wibergs stiftelse
- Lars Jakobsson - Associate professor
- Maria Garcia Collado - PhD student
- Antonio Queiro Palou - PhD student
- Anna-Liisa Luik - Postdoc
- Franziska Kohl - PhD student (employed by AstraZeneca, Mölndal)
- Nicole Laszlo - Medical student
- Stephanie Preuss - Master student
- Yixin Wang - Postdoc
- Yi Jin - Postdoc
- Anne-Claire Duches - Postdoc
- David Kaluza - Postdoc - EMBO Fellow
- Leonie Schoch - Erasmus student
- Zacharias Iredahl - Biomed/Medical student
- Oguzhan Kaya – Erasmus student
- Mikhail Burmakin – Postdoc, Lab manager