IMPE Abstracts

Background: Fetal growth restriction (FGR) has been suggested to cause persistent effects long after birth, namely fetal programming (FP). Although FP has drawn attention, a number of questions remain to be answered. One of the major questions is time dependency, i.e., whether the timing when FP occurs would affect the outcome after birth. Indeed, in neonates born small for gestational age (SGA), a consequence of FGR, the potential of catch-up growth which usually occurs during the first three years of life is lower in the preterm neonates than that in the term neonates. We previously showed that umbilical cord-derived mesenchymal stem cells (UCMSCs) could be an in vitro model reflecting FP. MSCs have the capabilities to differentiate into adipocyte, chondrocyte, and osteocyte, and precise analyses of MSC would provide insights into the pathophysiology of post-natal growth problems. By using UCMSCs, we aimed to clarify differences on FP caused by FGR according to the gestational age.

Material and Method: UCMSCs were established from twenty neonates of four groups classified according to their perinatal history: term/preterm, and SGA/AGA (adequate for gestational age). The criteria of SGA and preterm were birth weight <10% tile, and <32 weeks of gestational age, respectively. We analyzed the gene expression profile using RNA sequence (RNAseq) and methylation status using Reduced Representation Bisulfite Sequencing (RRBS).

Result: The gene expression profiles of USMSCs revealed distinctive characteristics among each group, namely TA (Term AGA), TS (Term SGA), PA (Preterm AGA), and PS (Preterm SGA). In comparison between PS and TS, more than a thousand genes expression was significantly changed (P<0.05, and fold change: FC >2 or <1/2). Based on the two-way ANOVA analysis of the four groups, we narrowed down the 200 genes whose expression significantly changed between PS and TS, but not PA and TA. GO analysis showed annotations like “tissue morphogenesis”, “endothelium development”, and “renal system development” were enriched in PS. In DisGeNET database analysis, “Vascular Diseases”, “Weight Gain”, “Pulmonary Hypertension”, and “Cerebral Infarction” were enriched in PS. RRBS analysis verified the results of RNA-seq in the difference of methylation.

Discussion: This study revealed that FP due to FGR would affect the characteristics of UCMSCs in a time dependent manner. This result would explain the difference in clinical features between preterm SGA and term SGA, such as growth and metabolic problems of the post-natal period, especially in preterm SGA infants.