Maternal undernutrition induces cell signalling and metabolic dysfunction in undifferentiated mouse embryonic stem cells
Maternal undernutrition induces cell signalling and metabolic dysfunction in undifferentiated mouse embryonic stem cells
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. Graphical Abstract: [Figure not available: see fulltext.]
Cell signalling, DOHaD, Glucose metabolism, MAPK pathway, Maternal low protein diet, Metabolomics, Mouse ES cells, RNAseq
Khurana, Pooja
29339a46-2280-4378-be73-0b412e365006
Cox, Andrew Lee
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Islam, Barira
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Eckert, Judith
729bfa49-7053-458d-8e84-3e70e4d98e57
Willaime-Morawek, Sandrine
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0
Gould, Joanna Mary
96c504c1-273b-4104-98e6-87931fe763bf
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
McHugh, Patrick C
8495a0a9-d249-4f30-9464-16ff570b0656
Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03
15 December 2022
Khurana, Pooja
29339a46-2280-4378-be73-0b412e365006
Cox, Andrew Lee
71676dd2-b6e5-4356-893b-01e80c134cf5
Islam, Barira
51565bbb-62f7-4b49-9f90-1fe65352cf28
Eckert, Judith
729bfa49-7053-458d-8e84-3e70e4d98e57
Willaime-Morawek, Sandrine
24a2981f-aa9e-4bf6-ad12-2ccf6b49f1c0
Gould, Joanna Mary
96c504c1-273b-4104-98e6-87931fe763bf
Smyth, Neil
0eba2a40-3b43-4d40-bb64-621bd7e9d505
McHugh, Patrick C
8495a0a9-d249-4f30-9464-16ff570b0656
Fleming, Thomas
2abf761a-e5a1-4fa7-a2c8-12e32d5d4c03
Khurana, Pooja, Cox, Andrew Lee, Islam, Barira, Eckert, Judith, Willaime-Morawek, Sandrine, Gould, Joanna Mary, Smyth, Neil, McHugh, Patrick C and Fleming, Thomas
(2022)
Maternal undernutrition induces cell signalling and metabolic dysfunction in undifferentiated mouse embryonic stem cells.
Stem Cells Reviews and Reports.
(doi:10.1007/s12015-022-10490-1).
Abstract
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. Graphical Abstract: [Figure not available: see fulltext.]
Text
Khurana, Cox, Islam et al 2022
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Accepted/In Press date: 5 December 2022
e-pub ahead of print date: 15 December 2022
Published date: 15 December 2022
Additional Information:
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.
Publisher Copyright:
© 2022, The Author(s).
Keywords:
Cell signalling, DOHaD, Glucose metabolism, MAPK pathway, Maternal low protein diet, Metabolomics, Mouse ES cells, RNAseq
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Local EPrints ID: 473668
URI: http://eprints.soton.ac.uk/id/eprint/473668
ISSN: 2629-3277
PURE UUID: 548e0a9c-e65f-427d-be93-17901051c6f8
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Date deposited: 27 Jan 2023 17:34
Last modified: 17 Mar 2024 03:13
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Author:
Pooja Khurana
Author:
Andrew Lee Cox
Author:
Barira Islam
Author:
Joanna Mary Gould
Author:
Patrick C McHugh
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