Activation of fetal-like molecular programs during regeneration in the intestine and beyond.

Tissue regeneration after damage is generally thought to involve the mobilization of adult stem cells that divide and differentiate into progressively specialized progeny. However, recent studies indicate that tissue regeneration can be accompanied by reversion to a fetal-like state. During this process, cells at the injury site reactivate programs that operate during fetal development but are typically absent in adult homeostasis. Here, we summarize our current understanding of the molecular signals and epigenetic mediators that orchestrate "fetal-like reversion" during intestinal regeneration. We also explore evidence for this phenomenon in other organs and species and highlight open questions that merit future examination.

MAGIC matrices: freeform bioprinting materials to support complex and reproducible organoid morphogenesis.

Organoids are powerful models of tissue physiology, yet their applications remain limited due to a lack of complex tissue morphology and high organoid-to-organoid structural variability. To address these limitations we developed a soft, composite yield-stress extracellular matrix that supports freeform 3D bioprinting of cell slurries at tissue-like densities. Combined with a custom piezoelectric printhead, this platform allows more reproducible and complex morphogenesis from uniform and spatially organized organoid "seeds." At 4 °C the material exhibits reversible yield-stress behavior to support long printing times without compromising cell viability. When transferred to cell culture at 37 °C, the material cross-links and exhibits similar viscoelasticity and plasticity to basement membrane extracts such as Matrigel. We use this setup for high-throughput generation of intestinal and salivary gland organoid arrays that are morphologically indistinguishable from those grown in pure Matrigel, but exhibit dramatically improved homogeneity in organoid size, shape, maturation time, and budding efficiency. The reproducibility of organoid structure afforded by this approach increases the sensitivity of assays by orders of magnitude, requiring less input material and reducing analysis times. The flexibility of this approach additionally enabled the fabrication of perfusable intestinal organoid tubes. Combined, these advances lay the foundation for the efficient design of complex tissue morphologies in both space and time.

Epithelial zonation along the mouse and human small intestine defines five discrete metabolic domains.

A key aspect of nutrient absorption is the exquisite division of labour across the length of the small intestine, with individual nutrients taken up at different proximal:distal positions. For millennia, the small intestine was thought to comprise three segments with indefinite borders: the duodenum, jejunum and ileum. By examining the fine-scale longitudinal transcriptional patterns that span the mouse and human small intestine, we instead identified five domains of nutrient absorption that mount distinct responses to dietary changes, and three regional stem cell populations. Molecular domain identity can be detected with machine learning, which provides a systematic method to computationally identify intestinal domains in mice. We generated a predictive model of transcriptional control of domain identity and validated the roles of Ppar-δ and Cdx1 in patterning lipid metabolism-associated genes. These findings represent a foundational framework for the zonation of absorption across the mammalian small intestine.