Dr. Stephen C Land

Senior Lecturer

Address:

Division of Cardiovascular and Diabetes Medicine
Medical Research Institute
Ninewells Hospital and Medical School
University of Dundee
Dundee
DD1 9SY

Phone Number:

+(44) 01382 383356

Email Address:

s.c.land@dundee.ac.uk

Biography

Dr. Land gained a BSc Hons in Zoology (Environmental Physiology) from Aberdeen University in 1988 and subsequently won a Commonwealth Scholarship to study for a PhD investigating the control of metabolic dormancy under Prof. Peter Hochachka at the University of British Columbia, Vancouver, Canada. In 1995 he took up a postdoctoral position at the NIH-NCRR BioCurrents Research Center at the Marine Biological Laboratory, Woods Hole, USA, investigating non-invasive methods for measuring cellular oxygen and ion fluxes using a self-referencing electrode technique. He moved to Dundee in 1997 to take up a lectureship investigating pulmonary ion transport and oxygen sensing mechanisms in fetal lung development and these research themes have since evolved to encompass studies that examine how airway and vascular growth is co-ordinated in the fetal lung and also how these processes become altered in diseases that fundamentally alter lung architecture.

Research

Research in the Land group covers 3 major themes:

  1. Co-ordination of Airway and Vascular Growth in the Fetal Lung.

Proper lung function requires a branched network of airway and vascular tubes which dissipate resistance to blood and gas movement to the site of gas exchange in the alveolus.  The development of this network is governed by cues which control the duration of tubular out-growth and which induce, orientate and down-size each subsequent branch generation.  Our research has established that one key regulator of this process, Sprouty2, co-ordinates vascular and airway growth by controlling the activity of Hypoxia Inducible Factors (HIFs) in response to the primary cue for airway outgrowth, Fibroblast Growth Factor-10 (FGF-10). This has led us to investigate novel functions of Sprouty2 as an epigenetic regulator of key vascular signalling genes (e.g. Vascular Endothelial Growth Factor (VEGF)) and has wide relevance for the understanding of vascular patterning in development and in diseases such as diabetes and cancer. Our continuing research studies the broader role of Sprouty and its related proteins in the epigenetic control of nuclear events in response to growth factors, inflammation and environmental stressors such as hypoxia.  

Figure 1:  Spry2 co-ordinates airway and vascular growth during lung development.  Right hand panel shows an embryonic stage rat lung where perfused vasculature can be seen within the mesenchyme surrounding the airway branches and proximal to the airway tip (red hue). Foregut (Fg) is shown displaced to left of lung. Signaling in three zones of airway and vascular growth (A-C) are indicated in the left hand panel.  Zone A: FGF-10 is expressed in the mesenchyme ahead of nascent airway buds and diffuses towards the airway epithelium. Zone B: FGF-10 induces FGFR2b autophosphorylation and signaling to Spry2 whose activation inhibits signaling to the ERK1/2 pathway and also induces TSC2 clearance enabling Rheb to bind GTP and activate mTORC1.  Zone C: mTORC1 promotes transcriptional activity of hypoxia-stabilised HIF-1alpha by interaction with its FVMVL TOS motif. This augments the expression and secretion of VEGF-A into the surrounding mesenchyme so providing the primary angiogenic cue which sustains vascular growth along with that of the airway. 

 

  1. Mechanism of pulmonary cyst formation in Birt-Hogg-Dubé Syndrome (BHD).

Birt-Hogg-Dubé syndrome is an autosomal dominant disorder that is linked to frame-shift or missense mutations in the Folliculin gene (Flcn) and/or its interacting partners, FNIP1 and FNIP2. This causes a range of systemic disorders that typically include fibrofolliculomas on the face and chest, renal carcinoma, pulmonary cysts and pneumothorax. In collaboration with groups around the UK and Europe we are exploring the process of lung cyst formation and identifying therapies which could be adapted to an inhaler format to arrest or reverse this process. Key pathways under investigation include VEGF/VEGF-receptor signalling between pulmonary epithelium and vasculature and the regulation of intracellular trafficking events that determine cell polarity.

Figure 2: VEGF receptor-2 (VEGFR2) trafficking in ciliated primary human nasal epithelial cells.  A. Stationary image from live-video showing ciliary trafficking of a GFP tagged growth factor (VEGFR2-GFP, arrows) in ciliated human nasal epithelial cells.  B. VEGFR2 is transported out of cilia upon stimulation with VEGF-A (red, white arrows).  Cilia are stained with acetylated alpha-tubulin (green) and the cell membrane is delineated with a dotted line. Images are a 3-dimensional reconstruction from z-stack confocal images.

 

 

 

  1. Human Nasal Epithelial Cells as a Model for Studying Rare Genetic Disease.

Our research on BHD syndrome has identified a need for rare disease culture models that carry the true genotype of the donor (so-called “near-patient” or “patient-centred” models). We have developed a method for culturing cells from tissue that is lightly brushed from the back of the nose. This approach is painless, can be applied safely to volunteer patients of any age regardless of disease condition and yields a mixed population of epithelial and fibroblast cells types that can be grown in culture to model different aspects of lung anatomy and physiology.  We are collaborating with the Tayside Tissue Bank to establish methods of cryopreserving immortalised forms of these cells to establish a unique repository of genetically relevant, viable, cellular material as an international research resource.

Figure 3. Human nasal brush biopsies yield cells with stem and epithelial properties. A. Basal cells proliferate in culture to form a mixed population of stem and epithelioid cells. B. Polarised HNE cells generate a transepithelial voltage difference (Vte) and resistance (Rte). The spontaneous current is blocked by Amiloride (ENaC inhibitor) and subsequent Foskolin evokes a Cl- current that is inhibited by Inh-172 (CFTR inhibitor). Washes confirm sustained integrity of the monolayer. Ion transport can be studied in spheroids using ion-sensitive dyes (right). Here, ciliated cuboid spheroids loaded with Na+ sensitive CoroNa green extrude Na+ from the lumen whereas non-ciliated, cystic spheroids display uncompensated Na+ accumulation (green) typical of mis-regulated ion transport. C. Basal cells differentiate to form a polarised monolayer composed of ciliated (green, acetylated tubulin) and non-ciliated epithelial cells when at ALI. Blue, DAPI. Expanded image gives structural detail (cilia, green, acetylated tubulin) and ciliary base plate (red, folliculin). D. Differentiated HNE can be grown as polarised ciliated  spheroids with a fluid-filled lumen. 3D reconstruction of Z-stacks. Staining as in C.

Publications

(Selected from 50 Peer Reviewed Publications):

Land SC, Walker DJ, Du Q, Jovanović A. (2013) Cardioprotective SUR2A promotes stem cell properties of cardiomyocytes. Int J Cardiol. 168(5):5090-2.

Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala  RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA. (2013). Birt-Hogg-Dube syndrome is a novel ciliopathy. Hum Mol Genet. 22(21):4383-97.

Land SC (2012). Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists. Int J Physiol Pathophysiol Pharmacol. 4(2):59-73.

Watt GB, Ismail NA, Garcia Caballero A, Land SC, Wilson SM. (2012). Epithelial Na(+) channel activity in human airway epithelial cells: the role of Serum and glucocorticoid-inducible kinase 1Br J Pharmacol. In Press.

Land, S.C. Vascular Growth in the Fetal Lung.  In:  Vasculogenesis and Angiogenesis: From Embryonic Development to Regenerative Medicine. Ed D. T. and A Simionescu, Chapter 3, pp49-70, In Tech, ISBN 978-953-307-882-3, 2011.

Dunlop EA, Dodd KM, Land SC, Davies PA, Martins N, Stuart H, McKee S, Kingswood C, Saggar A, Corderio I, Medeira AM, Kingston H, Sampson JR, Davies DM, Tee AR. (2011). Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. Eur J Hum Genet. 19(7):789-95.

Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, Tee AR. (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene. 30(10):1159-73.

Scott CL, Walker DJ, Cwiklinski E, Tait C, Tee AR, Land SC. (2010). Control of HIF-1a and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clockAm J Physiol Lung Cell Mol Physiol. 299(4):L455-7.

Hunter MJ, Treharne KJ, Winter AK, Cassidy DM, Land S, Mehta A. (2010).  Expression of wild-type CFTR suppresses NF-kappaB-driven inflammatory signallingPLoS One. 2010; 5(7):e11598.

Land SC, Tee AR. (2007).  Hypoxia-inducible factor 1a is regulated by the mammalian target of rapamycin (mTOR) via an mTOR signaling motifJ Biol Chem. 2007;282(28):20534-43.

Rae C, Cherry JI, Land FM, Land SC. (2006) Endotoxin-induced nitric oxide production rescues airway growth and maturation in atrophic fetal rat lung explantsBiochem Biophys Res Commun.349(1):416-25.

Land SC, Rae C. (2005). iNOS initiates and sustains metabolic arrest in hypoxic lung adenocarcinoma cells: mechanism of cell survival in solid tumor coreAm J Physiol Cell Physiol.289(4):C918-33.

Land SC, Wilson SM. (2005).  Redox regulation of lung development and perinatal lung epithelial functionAntioxid Redox Signal. 7(1-2):92-107. Invited Review

Land SC. (2004) Hochachka's "Hypoxia Defense Strategies" and the development of the pathway for oxygen. Comp Biochem Physiol B Biochem Mol Biol. 139(3):415-33. Invited Review.

Land SC, Darakhshan F. (2004) Thymulin evokes IL-6-C/EBPb regenerative repair and TNF-a silencing during endotoxin exposure in fetal lung explants. Am J Physiol Lung Cell Mol Physiol.286(3):L473-87.

Ramminger SJ, Richard K, Inglis SK, Land SC, Olver RE, Wilson SM. (2004). A regulated apical Na(+) conductance in dexamethasone-treated H441 airway epithelial cells. Am J Physiol Lung Cell Mol Physiol. 287(2):L411-9.

Land SC. (2003). Oxygen-sensing pathways and the development of mammalian gas exchange. Redox Rep. 8(6):325-40. Invited Review

Richard K, Ramminger SJ, Inglis SK, Olver RE, Land SC, Wilson SM. (2003). O2 can raise fetal pneumocyte Na+ conductance without affecting ENaC mRNA abundance. Biochem Biophys Res Commun. 305(3):671-6.

Teaching

  • Lung Development and Function (Honours Life Sciences)
  • Regulation of Oxygen Utilisation (Honours Life Sciences)
  • Respiratory Physiology and Lung Mechanics (3rd Year Physiology)
  • Angiogenesis (Masters in Cancer Biology)
  • Undergraduate Advisor of Studies

PhD Supervision

David Walker.  A novel role for Sprouty2 in co-ordinating airway and vascular growth of the fetal lung. MSc, 2013

Gordon Watt.  The role of Serum- and Glucocorticoid kinase in the hormonal control of sodium transport in pulmonary epithelia. PhD, 2011

Conferences

Dec 2013: Folliculin regulates VEGF signalling in bronchial epithelium: Implications for cyst formation in the BHD lung. Epithelia and Smooth Muscle Interactions in Health and Disease, Physiological Society, Convention Centre Dublin, Dublin, Ireland

July 2013: Folliculin regulates epithelial-mesenchymal transition in airway epithelium: implications for cyst formation in the BHD lung. Fifth BHD Symposium and Second HLRCC Symposium, Louvre, Paris.