Lillycrop K.A.,Institute of Developmental science |
Burdge G.C.,University of Southampton
Journal of Nutrigenetics and Nutrigenomics | Year: 2011
Epigenetic processes which include DNA methylation, histone modification and miRNAs are integral in determining when and where specific genes are expressed. There is now increasing evidence that the epigenome is susceptible to a variety of environmental cues, such as nutrition, during specific periods of development. The changes induced by early-life nutrition may reflect an adaptive response of the foetus to environmental cues acting through the process of developmental plasticity. This may allow an organism to adjust its developmental programme resulting in long-term changes in its metabolism and physiology in order to be better matched to the future environment. However, when the future environment lies outside the anticipated range, metabolic and homoeostatic capacity will be mismatched with the environment and that individual will be at increased risk of developing a range of non-communicable diseases. Thus the environmental regulation of epigenetic processes is a central component in the developmental origins of non-communicable diseases and our understanding of these processes is, therefore, critical both for the identification of individuals at risk and for the development of new intervention strategies. Copyright © 2012 S. Karger AG, Basel.
Khan F.,University of Edinburgh |
Tare R.S.,Institute of Developmental science |
Kanczler J.M.,Institute of Developmental science |
Oreffo R.O.C.,Institute of Developmental science |
Bradley M.,University of Edinburgh
Biomaterials | Year: 2010
A combination of high-throughput material formulation and microarray techniques were synergistically applied for the efficient analysis of the biological functionality of 135 binary polymer blends. This allowed the identification of cell-compatible biopolymers permissive for human skeletal stem cell growth in both in vitro and in vivo applications. The blended polymeric materials were developed from commercially available, inexpensive and well characterised biodegradable polymers, which on their own lacked both the structural requirements of a scaffold material and, critically, the ability to facilitate cell growth. Blends identified here proved excellent templates for cell attachment, and in addition, a number of blends displayed remarkable bone-like architecture and facilitated bone regeneration by providing 3D biomimetic scaffolds for skeletal cell growth and osteogenic differentiation. This study demonstrates a unique strategy to generate and identify innovative materials with widespread application in cell biology as well as offering a new reparative platform strategy applicable to skeletal tissues. © 2009 Elsevier Ltd. All rights reserved.
Stead R.,Vascular Research Group |
Musa M.G.,Vascular Research Group |
Bryant C.L.,Vascular Research Group |
Lanham S.A.,Institute of Developmental science |
And 5 more authors.
Journal of Hypertension | Year: 2016
Objectives: The endothelium maintains vascular homeostasis through the release of endothelium-derived relaxing factors (EDRF) and endothelium-derived hyperpolarization (EDH). The balance in EDH:EDRF is disturbed in cardiovascular disease and may also be susceptible to developmental conditioning through exposure to an adverse uterine environment to predispose to later risk of hypertension and vascular disease. Methods: Developmentally conditioned changes in EDH:EDRF signalling pathways were investigated in cremaster arterioles (18-32μm diameter) and third-order mesenteric arteries of adult male mice offspring of dams fed either a fat-rich (high fat, HF, 45% energy from fat) or control (C, 10% energy from fat) diet. After weaning, offspring either continued on high fat or were placed on control diets to give four dietary groups (C/C, HF/C, C/HF, and HF/HF) and studied at 15 weeks of age. Results: EDH via intermediate (IK Ca) and small (SK ca) conductance calcium-activated potassium channels contributed less than 10% to arteriolar acetylcholine-induced relaxation in in-situ conditioned HF/C offspring compared with ∼60% in C/C (P<0.01). The conditioned reduction in EDH signalling in HF/C offspring was reversed in offspring exposed to a high-fat diet both before and after weaning (HF/HF, 55%, P<0.01 vs. HF/C). EDH signalling was unaffected in arterioles from C/HF offspring. The changes in EDH:EDRF were associated with altered endothelial cell expression and localization of IK Ca channels. Conclusion: This is the first evidence that EDH-mediated microvascular relaxation is susceptible to an adverse developmental environment through down-regulation of the IK Ca signalling pathway. Conditioned offspring exposed to a 'second hit' (HF/HF) exhibit adaptive vascular mechanisms to preserve dilator function. © Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
Cleal J.K.,Institute of Developmental science |
Glazier J.D.,University of Manchester |
Ntani G.,MRC Lifecourse Epidemiology Unit |
Crozier S.R.,MRC Lifecourse Epidemiology Unit |
And 9 more authors.
Journal of Physiology | Year: 2011
Fetal growth depends on placental transfer of amino acids from maternal to fetal blood. The mechanisms of net amino acid efflux across the basal membrane (BM) of the placental syncytiotrophoblast to the fetus, although vital for amino acid transport, are poorly understood. We examined the hypothesis that facilitated diffusion by the amino acid transporters TAT1, LAT3 and LAT4 plays an important role in this process, with possible effects on fetal growth. Amino acid transfer was measured in isolated perfused human placental cotyledons (n= 5 per experiment) using techniques which distinguish between different transport processes. Placental TAT1, LAT3 and LAT4 proteins were measured, and mRNA expression levels (measured using real-time quantitative-PCR) were related to fetal and neonatal anthropometry and dual-energy X-ray absorptiometry measurements of neonatal lean mass in 102 Southampton Women's Survey (SWS) infants. Under conditions preventing transport by amino acid exchangers, all amino acids appearing in the fetal circulation were substrates of TAT1, LAT3 or LAT4. Western blots demonstrated the presence of TAT1, LAT3 and LAT4 in placental BM preparations. Placental TAT1 and LAT3 mRNA expression were positively associated with measures of fetal growth in SWS infants (P < 0.05). We provide evidence that the efflux transporters TAT1, LAT3 and LAT4 are present in the human placental BM, and may play an important role in the net efflux of amino acids to the fetus. Unlike other transporters they can increase fetal amino acid concentrations. Consistent with a role in placental amino acid transfer capacity and fetal growth TAT1 and LAT3 mRNA expression showed positive associations with infant size at birth. © 2011 The Authors. Journal compilation © 2011 The Physiological Society.
Sengers B.G.,Institute of Developmental science |
Dawson J.I.,Institute of Developmental science |
Oreffo R.O.C.,Institute of Developmental science
Bone | Year: 2010
Skeletal regeneration and tissue engineering strategies rely critically on the efficient expansion of progenitor cell populations whilst simultaneously preserving multipotentiality and the ability to induce differentiation towards bone and cartilage. Cell population heterogeneity has a significant impact on this process, but is currently poorly quantified, hampering the interpretation of experimental results and the design of optimised expansion protocols. The objective of this study was to characterise individual human bone marrow stromal cell heterogeneity in terms of colony expansion potential. For this purpose, a novel two-stage CFU-F assay was developed in which cells from primary single cell-derived colonies were detached and reseeded again at clonal density as single cells to form new secondary colonies. This clearly demonstrated how secondary colony growth potential varies markedly both between and within primary colonies. Depending on the primary colony, cells either generated small secondary colonies only, or else a wide range of colony sizes. Using computational modelling it was shown how such colony heterogeneity could arise from hierarchical progenitor cell populations and what the limits of such a population structure were in explaining the experimental data. In addition the model demonstrated the significant potential impact of cell mobility on expansion potential and its implications for inducing population heterogeneity. This combined experimental-computational approach will ascertain the impact of cell culture protocols on the expansion potential and functional composition of heterogeneous progenitor populations. Such insights are likely to be of crucial importance for the success of skeletal regeneration strategies. © 2009 Elsevier Inc. All rights reserved.
Maiaru M.,University College London |
Tochiki K.K.,University College London |
Cox M.B.,University of Texas at El Paso |
Annan L.V.,University College London |
And 5 more authors.
Science Translational Medicine | Year: 2016
Polymorphisms in FKBP51 are associated with stress-related psychiatric disorders and influence the severity of pain symptoms experienced after trauma. We report that FKBP51 (FK506 binding protein 51) is crucial for the full development and maintenance of long-term pain states. Indeed, FKBP51 knockout mice, as well as mice in which silencing of FKBP51 is restricted to the spinal cord, showed reduced hypersensitivity in several persistent pain models in rodents. FKBP51 deletion did not compromise the detection of acute painful stimuli, a critical protective mechanism. Moreover, the intrathecal administration of the specific FKBP51 inhibitor SAFit2 reduced the severity of an established pain state, confirming the crucial role of spinal FKBP51 in nociceptive processing. Finally, glucocorticoid signaling, which is known to modulate persistent pain states in rodents, was impaired in FKBP51 knockout mice. This finding suggested that FKBP51 regulates chronic pain by modulation of glucocorticoid signaling. Thus, FKBP51 is a central mediator of chronic pain, likely in humans as well as rodents, and is a new pharmacologically tractable target for the treatment of long-term pain states.