TY - JOUR
T1 - Maternal Undernutrition Induces Cell Signalling and Metabolic Dysfunction in Undifferentiated Mouse Embryonic Stem Cells
AU - Khurana, Pooja
AU - Cox, Andrew
AU - Islam, Barira
AU - Eckert, Judith J
AU - Willaime-Morawek, Sandrine
AU - Gould, Joanna M
AU - Smyth, Neil R
AU - McHugh, Patrick C
AU - Fleming, Tom P
N1 - Funding Information:
This work was supported through the Biotechnology and Biological Sciences Research Council, UK (BBSRC; BB/F007450/1) to TPF, the European Union FP7-PEOPLE-2012-ITN EpiHealthNet programme (317146) and FP7-CP-FP Epihealth programme (278418) to TPF, a BBSRC DTA studentship to NRS, TPF and AC; the Centre for Biomarker Research, University of Huddersfield to PCM and BI; the Wessex Medical Research and Rosetrees Trust (M327-CD1) to SWM. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.
Funding Information:
We thank the University of Southampton Biomedical Research Facility staff for animal technical support, the Faculty of Medicine Flow Cytometry Unit and Biomedical Imaging Unit for staff support for FACS and confocal microscopy, respectively. We thank the technical support provided by Metabolon staff (www.metabolon.com) in the analysis of provided ESC lines. We would also like to thank members of the Centre for Biomarker Research (CeBioR) team at University of Huddersfield.
Publisher Copyright:
© 2022, The Author(s).
PY - 2023/4/1
Y1 - 2023/4/1
N2 - Peri-conceptional environment can induce permanent changes in embryo phenotype which alter development and associate with later disease susceptibility. Thus, mouse maternal low protein diet (LPD) fed exclusively during preimplantation is sufficient to lead to cardiovascular, metabolic and neurological dysfunction in adult offspring. Embryonic stem cell (ESC) lines were generated from LPD and control NPD C57BL/6 blastocysts and characterised by transcriptomics, metabolomics, bioinformatics and molecular/cellular studies to assess early potential mechanisms in dietary environmental programming. Previously, we showed these lines retain cellular and epigenetic characteristics of LPD and NPD embryos after several passages. Here, three main changes were identified in LPD ESC lines. First, their derivation capacity was reduced but pluripotency marker expression was similar to controls. Second, LPD lines had impaired Mitogen-activated protein kinase (MAPK) pathway with altered gene expression of several regulators (e.g., Maff, Rassf1, JunD), reduced ERK1/2 signalling capacity and poorer cell survival characteristics which may contribute to reduced derivation. Third, LPD lines had impaired glucose metabolism comprising reduced upstream enzyme expression (e.g., Gpi, Mpi) and accumulation of metabolites (e.g., glucose-6-P, fructose-6-P) above the phosphofructokinase (PFK) gateway with PFK enzyme activity reduced. ESC lines may therefore permit investigation of peri-conceptional programming mechanisms with reduced need for animal experimentation.
AB - Peri-conceptional environment can induce permanent changes in embryo phenotype which alter development and associate with later disease susceptibility. Thus, mouse maternal low protein diet (LPD) fed exclusively during preimplantation is sufficient to lead to cardiovascular, metabolic and neurological dysfunction in adult offspring. Embryonic stem cell (ESC) lines were generated from LPD and control NPD C57BL/6 blastocysts and characterised by transcriptomics, metabolomics, bioinformatics and molecular/cellular studies to assess early potential mechanisms in dietary environmental programming. Previously, we showed these lines retain cellular and epigenetic characteristics of LPD and NPD embryos after several passages. Here, three main changes were identified in LPD ESC lines. First, their derivation capacity was reduced but pluripotency marker expression was similar to controls. Second, LPD lines had impaired Mitogen-activated protein kinase (MAPK) pathway with altered gene expression of several regulators (e.g., Maff, Rassf1, JunD), reduced ERK1/2 signalling capacity and poorer cell survival characteristics which may contribute to reduced derivation. Third, LPD lines had impaired glucose metabolism comprising reduced upstream enzyme expression (e.g., Gpi, Mpi) and accumulation of metabolites (e.g., glucose-6-P, fructose-6-P) above the phosphofructokinase (PFK) gateway with PFK enzyme activity reduced. ESC lines may therefore permit investigation of peri-conceptional programming mechanisms with reduced need for animal experimentation.
KW - Maternal undernutrition
KW - Mouse Embryonic Stem Cells
KW - Embryo phenotype
KW - Embryonic stem cells (ESC)
KW - Cell signalling
KW - MAPK pathway
KW - Glucose metabolism
KW - Metabolomics
KW - DOHaD
KW - Maternal low protein diet
KW - Mouse ES cells
KW - RNAseq
UR - http://www.scopus.com/inward/record.url?scp=85143801682&partnerID=8YFLogxK
U2 - 10.1007/s12015-022-10490-1
DO - 10.1007/s12015-022-10490-1
M3 - Article
C2 - 36517693
VL - 19
SP - 767
EP - 783
JO - Stem Cell Reviews and Reports
JF - Stem Cell Reviews and Reports
SN - 2629-3269
IS - 3
ER -