title: Molecular pathways reflecting poor intrauterine growth are found in Wharton's jelly-derived mesenchymal stem cells.
abstract: OBJECTIVE
  Are molecular pathways reflecting the biology of small for gestational age (SGA) neonates preserved in umbilical cord-derived mesenchymal stem cells (MSCs)?
  
  
  CONCLUSIONS
  MSCs from SGA newborns were found to express an altered EGR-1-dependent gene network involved in the regulation of cell proliferation and oxidative stress.
  
  
  BACKGROUND
  Individuals with suboptimal intrauterine development are at greater risk of metabolic diseases such as type II diabetes, obesity and cardiovascular disease.
  
  
  METHODS
  Umbilical cords (n = 283) from the GUSTO (growing up in Singapore towards healthy outcomes) birth cohort study, and primary MSC isolates established from SGA and matched control cases (n = 6 per group), were subjected to gene expression analysis and candidate genes were studied for functional validation.
  
  
  METHODS
  Umbilical cord specimens were derived from babies born at the National University Hospital (NUH) in Singapore. Local ethical approval was obtained. MSC isolates were established in Wharton's jelly and molecular analysis was conducted by gene expression microarrays and RT-PCR. Cells from SGA and control groups were compared in the presence and absence of insulin and candidate gene function was studied via siRNA-mediated gene knockdown and over-expression experiments in MSCs.
  
  
  RESULTS
  Using repeated measure ANOVAs, proliferation rates of MSCs isolated from SGA neonates were found to be significantly increased (P < 0.01). In the absence of insulin, EGR-1 levels were found to be significantly reduced in the group of SGA-derived MSCs, whereas EGR-1 expression was found to be up-regulated in the same group in the presence of insulin (P < 0.01). EGR-1 was found to induce expression of COX-2 in the SGA group (P < 0.01) and both, EGR-1 and COX-2 stimulated glucose uptake in MSCs (P < 0.01). EGR-1 and COX-2 levels were associated in whole umbilical cords (n = 283, P < 0.01) and EGR-1 positively correlated with abdominal circumference and birthweight (n = 91, P < 0.01 and n = 91, P < 0.01).
  
  
  CONCLUSIONS
  Cell models may not entirely reflect the physiology of the host and patient follow-up studies will be necessary for further clinical validation.
  
  
  CONCLUSIONS
  Our study suggests that Wharton's jelly-derived MSCs are useful in identifying pathways specific for fetal growth restriction.
  
  
  BACKGROUND
  This work is supported by the Translational Clinical Research (TCR) Flagship Program on Developmental Pathways to Metabolic Disease funded by the National Research Foundation (NRF) and administered by the National Medical Research Council (NMRC), Singapore- NMRC/TCR/004-NUS/2008'. SICS Investigators are supported through the Agency for Science Technology and Research (A*STAR) funding. No potential conflicts of interest relevant to this article were reported.
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Rami
authors.initials: R
authors.lastname: Sukarieh
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Roy
authors.initials: R
authors.lastname: Joseph
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Shi Chi
authors.initials: SC
authors.lastname: Leow
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Mona
authors.initials: M
authors.lastname: Löffler
authors.affiliation: Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Izzuddin M
authors.initials: IM
authors.lastname: Aris
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Jun Hao
authors.initials: JH
authors.lastname: Tan
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Teh
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
authors.forename: Joanna D
authors.initials: JD
authors.lastname: Holbrook
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Kai Lyn
authors.initials: KL
authors.lastname: Ng
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Yap Seng
authors.initials: YS
authors.lastname: Chong
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore Liggins Institute, University of Auckland, Auckland, New Zealand.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gluckman
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science Technology and Research (A*STAR), Singapore, Singapore walter_stunkel@sics.a-star.edu.sg.
authors.forename: Walter
authors.initials: W
authors.lastname: Stünkel
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D047109:Fetal Development; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D014470:Umbilical Cord / Q000166:cytology / Q000378:metabolism; D059631:Wharton Jelly / Q000166:cytology* / Q000378:metabolism
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D005947:Glucose
keywords: gene expression; insulin; stem cells