Gut Bioengineering Laboratory

Overview

The laboratory, led by Dr. Nima Saeidi, focuses on defining how mechanical cues and metabolic pathways converge to regulate intestinal stem cell (ISC) function, and how disruption of this mechanometabolic axis drives disease. The intestinal epithelium is one of the most rapidly renewing tissues in the body, yet the principles governing how physical forces are integrated with cellular metabolism to control stem cell fate remain poorly understood.

This team has established a new conceptual framework in which biomechanics actively rewires metabolic flux to determine stem cell behavior. A central discovery from the laboratory is that ISCs exhibit a unique metabolic dependency on GLUT1-mediated glucose uptake, channeling the majority of intracellular glucose into the pentose phosphate pathway to sustain de novo nucleotide biosynthesis. Disruption of this pathway impairs stem cell proliferation and epithelial regeneration, while nucleoside supplementation is sufficient to restore function, revealing a direct and targetable link between metabolism and stem cell fate. In parallel, they have shown that tissue mechanics—such as intestinal stiffening observed in aging and inflammatory conditions—profoundly alters ISC behavior through activation of mechanotransduction pathways including YAP and Piezo1, thereby coupling physical forces to metabolic reprogramming. To enable these discoveries, the group has developed innovative experimental and computational platforms, including planar “2.5D” open-lumen organoids and high-content phenotypic screening approaches integrated with machine learning-based image analysis. These systems have allowed the team to systematically dissect how mechanical and metabolic inputs interact across scales, from single cells to tissue-level organization. Looking forward, the goal is to build predictive, design-driven models of intestinal regeneration and disease by integrating mechanobiology, metabolism, and systems biology. By uncovering the fundamental rules governing mechanometabolic regulation, this work aims to identify new therapeutic strategies for conditions such as inflammatory bowel disease, aging-associated degeneration, and colorectal cancer.