Placenta · 2026
Fetal environment associated with small for gestational age birth transcriptionally primes umbilical cord mesenchymal stem cells toward osteogenic pathways with potentially impaired adipogenic differentiation.
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Yogi Analia, Noguchi Yusuke, Kirino Shizuka, Yamano Haruki, Adachi Eriko, Nakatani Hisae, Saito Yoko, Morioka Chikako, Hayata Mari, Sugie Manabu, Takasawa Kei, Morio Tomohiro, Takagi Masatoshi, Tsuji-Hosokawa Atsumi, Kashimada Kenichi
Аннотация
INTRODUCTION: Fetal programming is proposed to induce persistent changes in gene expression, influencing disease susceptibility later in life; however, separating environmental effects from genetic background remains challenging.
METHODS: To investigate genotype-independent effects of fetal growth restriction (FGR), we established human umbilical cord-derived mesenchymal stem cells (hUCMSCs) from six monozygotic twin pairs with ≥20% birth-weight discordance. The larger twin was appropriate for gestational age (AGA) and the smaller was small for gestational age (SGA). We performed paired transcriptomic analyses of hUCMSCs and after in vitro adipogenic differentiation.
RESULTS: Despite smaller intra-pair than inter-pair variation, SGA-derived hUCMSCs displayed distinct gene expression profiles relative to AGA co-twins. Gene set enrichment analysis revealed positive enrichment of osteogenesis- and glial proliferation-related gene sets, and negative enrichment of glycolysis and RNA processing in SGA cells. Distinct profiles were maintained after adipogenic differentiation. SGA-derived adipocytes demonstrated enrichment of extracellular matrix (ECM) remodeling-related gene sets, including matrix metalloproteinases, and reduced cytoplasmic translation. Given the small sample size, these findings are hypothesis-generating. Although mature adipocyte markers (PPARG, FABP4) were comparable between groups, the preadipocyte marker DLK1 was consistently higher (nominal P = 0.006) in SGA-derived adipocytes, suggesting potentially impaired maturation.
CONCLUSION: These exploratory findings suggest that FGR is associated with persistent genotype-independent alterations in gene expression and transcriptional priming in hUCMSCs. Enhanced bias toward osteogenesis-related gene set and altered ECM dynamics in SGA cells may compromise adipose tissue plasticity, providing insight into persistent gene expression which would shape the developmental origins of health and disease (DOHaD) hypothesis in humans.
METHODS: To investigate genotype-independent effects of fetal growth restriction (FGR), we established human umbilical cord-derived mesenchymal stem cells (hUCMSCs) from six monozygotic twin pairs with ≥20% birth-weight discordance. The larger twin was appropriate for gestational age (AGA) and the smaller was small for gestational age (SGA). We performed paired transcriptomic analyses of hUCMSCs and after in vitro adipogenic differentiation.
RESULTS: Despite smaller intra-pair than inter-pair variation, SGA-derived hUCMSCs displayed distinct gene expression profiles relative to AGA co-twins. Gene set enrichment analysis revealed positive enrichment of osteogenesis- and glial proliferation-related gene sets, and negative enrichment of glycolysis and RNA processing in SGA cells. Distinct profiles were maintained after adipogenic differentiation. SGA-derived adipocytes demonstrated enrichment of extracellular matrix (ECM) remodeling-related gene sets, including matrix metalloproteinases, and reduced cytoplasmic translation. Given the small sample size, these findings are hypothesis-generating. Although mature adipocyte markers (PPARG, FABP4) were comparable between groups, the preadipocyte marker DLK1 was consistently higher (nominal P = 0.006) in SGA-derived adipocytes, suggesting potentially impaired maturation.
CONCLUSION: These exploratory findings suggest that FGR is associated with persistent genotype-independent alterations in gene expression and transcriptional priming in hUCMSCs. Enhanced bias toward osteogenesis-related gene set and altered ECM dynamics in SGA cells may compromise adipose tissue plasticity, providing insight into persistent gene expression which would shape the developmental origins of health and disease (DOHaD) hypothesis in humans.