Maternal Endocrine and Vascular Perturbations Reprogram the Transcriptomic and Secretory Profile of Perinatal Stem...

Perinatal mesenchymal stem cells (MSCs) are characterized by high phenotypic plasticity, allowing them to dynamically adapt to microenvironmental stimuli. However, the extent to which maternal pathophysiology and clinical history in vivo permanently alter their biological properties remains poorly understood. The aim of this study is to determine the influence of the maternal in vivo environment-including vascular stress (gestational hypertension), metabolic stress (hypothyroidism), and obstetric history (miscarriages, stillbirths)-on the transcriptomic, proteomic, and epigenetic profiles of growth factors in umbilical cord blood stem cells (UC-MSCs) and human milk stem cells (MM-MSCs). UC-MSCs (n = 51) and MM-MSCs (n = 78) were isolated from eligible donors. Global transcriptomic pathways associated with maternal hypertension were examined in UC-MSCs using Affymetrix expression microarrays. Targeted polymerase chain reaction (qPCR) validation was performed in both cell sources for key growth factors and receptors and for microRNA-155 in MM-MSCs. Paracrine protein concentrations (HGF, IGF-1, VEGF) in whole milk were quantified using ELISA. Microarray screening demonstrated that maternal hypertension is associated with a transcriptomic shift in the UC-MSCs towards a profibrotic signature, marked by an increased expression of the canonical Wnt signaling pathway and structural components of the extracellular matrix, while simultaneously suppressing the expression of genes associated with cell migration networks. qPCR confirmed that maternal hypertension is associated with significantly reduced FGFR1 expression and a downward trend in EGF and HGF in UC-MSCs, while correlating with an asymmetric response in MM-MSCs. Maternal hypothyroidism was linked to a transcriptomic profile suggestive of a rescue response (a trend toward increased IGF1 and EGF expression) in UC-MSCs, in contrast to a potential paracrine translation deficit (trends toward reduced VEGF, HGF, and IGF-1 protein levels) in the milk matrix. Importantly, a history of miscarriage correlated with alterations in the cellular mechanism of MM-MSCs (a trend toward increased IGF1 and EGF mRNA expression), while previous stillbirths were associated with a systemic, threefold increase in free IGF-1 protein concentration in whole milk. This paracrine dynamic strongly correlated with miR-155 expression, suggesting a potential regulatory role in the lactation niche. Our findings suggest that the molecular and epigenetic makeup of perinatal stem cell niches is dynamically and persistently associated with the mother's somatic health and reproductive history. This tissue-specific plasticity provides robust molecular support for the DOHaD paradigm, indicating that offspring stem cell profiles may directly reflect the maternal inheritance in vivo.