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Sleeve Gastrectomy Reveals the Plasticity of the Human Gastric Epithelium

ABSTRACT: Gastric acidity is essential for the function of the human stomach. pH homeostasis is facilitated by gastrin, a hormone secreted from the gastric antrum in response to a rise in pH, leading to acid secretion from the gastric corpus. Sleeve gastrectomy (SG), a bariatric surgery in which 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. We used histology and single-cell RNA sequencing to study the gastric antrum and corpus epithelium of naïve patients, and of patients who underwent SG years earlier. SG was associated with an increase in a sub-population of acid-secreting parietal cells which overexpress respiratory enzymes and carbonic anhydrase, and an increase in the fraction of histamine-secreting enterochromaffin-like cells (ECLs). Notably, ECLs of SG-operated patients over-expressed genes coding for biosynthesis of neuropeptides and of serotonin. Mathematical modeling of pH homeostasis by gastrin showed that fasting pH is not sensitive to nearly all model parameters. Robustness is a result of the ability of gastrin to induce acid secretion as well as increase the number of ECLs and parietal cells, a feedback analogous to a non-linear proportional and integral feedback control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative predictions of the model on the gastric response to SG were validated in patients: SG induced a 5-fold increase in blood gastrin levels as early as one day post-surgery, and an over 30% increase in the number of parietal cells and ECLs per gland years after surgery. Together, these empirical and modeling data demonstrate how the human gastric epithelium remodels following SG at the molecular and cellular levels, and more generally how trophic hormones such as gastrin enable robust adaptation of tissue function to meet physiological demand.

ORGANISM(S): Homo sapiens

PROVIDER: GSE263018 | GEO | 2024/12/15

REPOSITORIES: GEO

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Project description:The glandular stomach is comprised of two anatomically and functionally distinct epithelial tissues termed corpus and antrum. While these compartments continuously regenerate to ensure normal organ function, our understanding of the molecular and cellular determinants that maintain these tissues remains incomplete. Here, we established an unbiased account of all gastric epithelial cells of the mouse corpus and antrum using single cell RNA-sequencing, allowing us to compare these adjacent epithelia and their stem cell compartments. Our data reveals that epithelial cell types with equivalent functional roles in the corpus and antrum utilize similar transcriptional programs, and our results support the existence of two discernible stem cell populations within the gland base and isthmus regions of these tissues. To study isthmus stem cells, typically underrepresented in conventional, gland base-enriched organoid cultures, we developed a novel 2D monolayer culture system to propagate mouse and human gastric epithelia. These 2D cultures expand indefinitely via Lgr5- isthmus-like cells and maintain the ability to differentiate into diverse gastric cell types. While 2D corpus and antrum cultures were transcriptionally similar, they retained a molecular memory and differentiation bias that mirrored their tissue of origin. Furthermore, gastric 2D cultures could be readily and reversibly converted into conventional 3D organoids, highlighting the remarkable plasticity of undifferentiated stomach epithelial cells. Finally, we utilized the 2D culture system to show that rare primary epithelial cells with high levels of Sox2 expression, previously hypothesized to be gastric stem cells, most closely resembled enterochromaffin (EC) cells and Sox2 is both necessary and sufficient to generate EC cells in vivo. Together, our data (i) provide important insights into the basis of gastric epithelial regeneration and differentiation, (ii) establish a tractable 2D culture system to capture and manipulate primary gastric isthmus stem cells in vitro and (iii) uncover a role for the stem cell factor Sox2 during EC cell specification.

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Sleeve Gastrectomy Reveals the Plasticity of the Human Gastric Epithelium

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