Early-Life Nutritional Disruption Reshapes Gastric Epithelial Development Through Coordinated Changes in the Dynamics...

Gastric gland cells originate from two proliferative niches: the main rapid one in the isthmus, and the slow secondary one in the base. However, while nutrition is dependent on breastfeeding, the proliferative niches are not established, and proliferation occurs along the gland. Currently, we investigated the influence of early weaning (EW) on shaping gastric proliferative niches and their signaling. Wistar rats were separated into suckling (S) and EW groups on postnatal day (PND) 15 for gastric mucosa collection. BrdU was administered (PND 14 and 15) and as it diluted between daughter-cells we evaluated migration and differentiation. In parallel EdU incorporation was used to identify cells during S phase. Through these tools, we studied the different profiles of BrdU/EdU dual labeling at 18, 21 and 30 PND. At 18 PND, EW decreased BrdU+ population (p < 0.0001 vs. S group) in the upper and bottom gland areas (p < 0.05). The BrdU + /EdU+ cells were concentrated in the upper gland, where we recorded a larger EdU+ population after EW (p < 0.05). On PND 30, EW decreased BrdU+ cells in the gland (p < 0.05), whereas EdU+ cells were more numerous in the isthmus. At 18 PND, EW reduced Wnt3, Notch1, and Notch2 expressions (p < 0.05), while increasing Bmp2. In contrast, at 60 PND, Axin2, Notch1, and Notch2 transcripts were elevated after EW (p < 0.05). Notch1 and Notch2 distribution indicated that EW might shift Notch2 to the upper gland, potentially affecting the fate of progenitor cells in pups. In silico analyses showed that zymogenic cells are in a renewal-promoting environment, while parietal cells contribute to differentiation and signaling. Therefore, EW restricted the proliferative activity to the isthmus, altering the spatiotemporal expression of genes involved in stemness and differentiation, and reshaped the distribution of Notch receptors, without affecting the distribution of its downstream effector Hes1. These spatially organized molecular landscapes are crucial for proper epithelial renewal and function, and our data suggest that early nutritional disruption reprograms these niches with long-term consequences.