Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.
Project description:Tissue regeneration is a process that recapitulates the molecular and mechanical aspects of development and evolution. We use the wound-induced hair neogenesis (WIHN) model to investigate the mechanical and molecular responses of the laboratory (Mus) and African spiny (Acomys) mice. Laboratory and spiny mice showed an opposite trend of spatiotemporal morphogenetic field for WIHN during wound healing, and wound stiffness gradient across the whole wound bed predicated pattern of hair formation. Using bulk and single-cell RNA-seq analysis and K14-Cre-Twist1 transgenic mice, we identified the central role of the Twist1 pathway as the mediator of epidermal-dermal interaction and the emergence of periodic hair primordia. Lastly, we generated a Turing model with an underlying measure of stiffness to support a two-scale tissue mechanic model to explain the setup of a morphogenetic field from a wound bed (mm scale) or periodically arranged hair primordia from a morphogenetic field (μm scale). Delineating the common and distinct chemo-mechanical events during regenerative wound healing between laboratory and African spiny mice reveal its evo-devo advantages, which provide new perspectives for regenerative medicine.
Project description:Intestinal organoids are complex three-dimensional structures that mimic cell type composition and tissue organization of the intestine by recapitulating the self-organizing capacity of cell populations derived from a single stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical cyst differentiate into Paneth cells, which in turn generates the stem cell niche and leads to asymmetric structures such as crypts and villi. We here combine a quantitative single-cell gene expression and imaging approach to characterize the development of intestinal organoids from a single cell. We show that intestinal organoid development follows a regeneration process driven by transient Yap1 activation. Cell-to-cell variability in Yap1, emerging in symmetrical cysts, initiates a Notch/Dll1 lateral inhibition event driving the symmetry-breaking event and the formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behavior resulting in the formation of complex multicellular asymmetric structures.
Project description:Intestinal organoids are complex three-dimensional structures that mimic cell type composition and tissue organization of the intestine by recapitulating the self-organizing capacity of cell populations derived from a single stem cell. Crucial in this process is a first symmetry-breaking event, in which only a fraction of identical cells in a symmetrical cyst differentiate into Paneth cells, which in turn generates the stem cell niche and leads to asymmetric structures such as crypts and villi. We here combine a quantitative single-cell gene expression and imaging approach to characterize the development of intestinal organoids from a single cell. We show that intestinal organoid development follows a regeneration process driven by transient Yap1 activation. Cell-to-cell variability in Yap1, emerging in symmetrical cysts, initiates a Notch/Dll1 lateral inhibition event driving the symmetry-breaking event and the formation of the first Paneth cell. Our findings reveal how single cells exposed to a uniform growth-promoting environment have the intrinsic ability to generate emergent, self-organized behavior resulting in the formation of complex multicellular asymmetric structures.
Project description:The human embryo breaks symmetry to form the anterior-posterior axis of the body. As the embryo elongates along this axis, progenitors in the tailbud give rise to tissues that generate the spinal cord, skeleton, and musculature. This raises the question of how the embryo achieves axial elongation and patterning. While ethics necessitate in vitro studies, the variability of organoid systems has hindered mechanistic insights. Here we developed a bioengineering and machine learning framework that optimizes symmetry breaking by tuning the spatial coupling between human stem cell-derived organoids. This framework enabled the reproducible generation of axially elongating organoids, each possessing a tailbud and neural tube. We discovered that an excitable system composed of WNT/FGF signaling drives elongation through induction of a neuromesodermal progenitor (NMP)-like signaling center. We discovered that instabilities in the excitable system are suppressed by secreted WNT inhibitors. Absence of these inhibitors led to ectopic tailbuds and branches. Our results identify mechanisms governing stable human axial elongation.