Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.
Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Assistance Publique - Hôpitaux de Paris, Service de Réanimation et Pédiatrie Néonatales, Groupe Hospitalier Robert Debré, Paris, France.|Université Paris Diderot, Paris, France.|Fondation PremUp, Paris, France.
Aline
A
Rideau Batista Novais
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Fondation PremUp, Paris, France.
Hoa
H
Pham
Laboratory for Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.|Division of Development and Growth, Department of Child and Adolescent Medicine, Geneva University Hospital and School of Medicine, Geneva, Switzerland.
Yohan
Y
Van de Looij
Institut Langevin, CNRS UMR 7587, Inserm U979, ESPCI ParisTech, PSL Research University, Paris, France.
Miguel
M
Bernal
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Fondation PremUp, Paris, France.
Jerome
J
Mairesse
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Fondation PremUp, Paris, France.|Université Paris-Descartes, Paris, France.|Assistance Publique - Hôpitaux de Paris, Service de Médecine et Réanimation Néonatales de Port-Royal, Groupe Hospitalier Cochin, Broca, Hôtel-Dieu, Paris, France.
Elodie
E
Zana-Taieb
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Fondation PremUp, Paris, France.
Marina
M
Colella
Fondation PremUp, Paris, France.|Université Paris-Descartes, Paris, France.|Assistance Publique - Hôpitaux de Paris, Service de Médecine et Réanimation Néonatales de Port-Royal, Groupe Hospitalier Cochin, Broca, Hôtel-Dieu, Paris, France.
Pierre-Henri
PH
Jarreau
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Fondation PremUp, Paris, France.
Julien
J
Pansiot
Institut Cochin, Inserm U1016, UMR8104 CNRS, Paris, France.
Florent
F
Dumont
Division of Development and Growth, Department of Child and Adolescent Medicine, Geneva University Hospital and School of Medicine, Geneva, Switzerland.
Stéphane
S
Sizonenko
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Université Paris Diderot, Paris, France.|Fondation PremUp, Paris, France.
Pierre
P
Gressens
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France.|Université Paris Diderot, Paris, France.|Fondation PremUp, Paris, France.
Christiane
C
Charriaut-Marlangue
Institut Langevin, CNRS UMR 7587, Inserm U979, ESPCI ParisTech, PSL Research University, Paris, France.
Mickael
M
Tanter
Institut Langevin, CNRS UMR 7587, Inserm U979, ESPCI ParisTech, PSL Research University, Paris, France.
Charlie
C
Demene
Institut Cochin, Inserm U1016, UMR8104 CNRS, Paris, France.
Daniel
D
Vaiman
Institut National de la Santé et de la Recherche Médicale (Inserm) U1141, Paris, France. olivier.baud@rdb.aphp.fr.|Assistance Publique - Hôpitaux de Paris, Service de Réanimation et Pédiatrie Néonatales, Groupe Hospitalier Robert Debré, Paris, France. olivier.baud@rdb.aphp.fr.|Université Paris Diderot, Paris, France. olivier.baud@rdb.aphp.fr.|Fondation PremUp, Paris, France. olivier.baud@rdb.aphp.fr.
Olivier
O
Baud
D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000378:metabolism*; D004676:Myelin Basic Protein / Q000378:metabolism; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000187:drug effects; D000076104:Oligodendrocyte Transcription Factor 2 / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism*; D011247:Pregnancy; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000502:physiology*; D000099216:Chondroitin Sulfate Proteoglycan 4
D025601:Adenomatous Polyposis Coli Protein; D000941:Antigens; D015703:Antigens, CD; D016207:Cytokines; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D000076104:Oligodendrocyte Transcription Factor 2; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4
myelination; neuroinflammation; neuroprotection; prenatal insult