Just Begin Again
I took a definite break over the last couple of weeks...and felt the accumulating weight of guilt of not doing something I committed to do. To the point that I was thinking Why Bother. But instead I'm just going to look those weeks in the eye, acknowlege they passed, and begin again.....
Last night we watched White Noise which I found to be one of those movies that I didn't know what was going on during it, but afterwards is making me think and is very meta. "I am tentatively scheduled to die" is my favorite line and I might just have to read the book. I get the sense it's a look at our obsession to identify the point of all things while also our obsession to distract ourselves from identifying the point of all things.
Now, for a sharp turn, on to Abstracts!
Happy 2023 and Tentatively Living!
Abstract 2023-01 Machine learning directed organoid morphogenesis uncovers an excitable system driving human axial elongation
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 axial tissues that generate the spinal cord, skeleton, and musculature. The mechanisms underlying human axial elongation are unknown. While ethics necessitate in vitro studies, the variability of human 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 pluripotent stem cell-derived organoids. This framework enabled the reproducible generation of hundreds of axially elongating organoids, each possessing a tailbud and an epithelial neural tube with a single lumen. We discovered that an excitable system composed of WNT and FGF signaling drives axial elongation through the induction of a signaling center in the form of neuromesodermal progenitor (NMP)-like cells. The ability of NMP-like cells to function as a signaling center and drive elongation is independent of their potency to generate mesodermal cell types. We further discovered that the instability of the underlying excitable system is suppressed by secreted WNT inhibitors of the secreted frizzled-related protein (SFRP) family. Absence of these inhibitors led to the formation of ectopic tailbuds and branches. Our results identify mechanisms governing stable human axial elongation to achieve robust morphogenesis.
Abstract 2023-02 Coupled organoids reveal that signaling gradients drive traveling segmentation clock waves during human axial morphogenesis
Axial development of mammals is a dynamic process involving several coordinated morphogenetic events including axial elongation, somitogenesis, and neural tube formation. How different signals control the dynamics of human axial morphogenesis remains largely unknown. By inducing anteroposterior symmetry breaking of spatially coupled epithelial cysts derived from human pluripotent stem cells, we were able to generate hundreds of axially elongating organoids. Each organoid was composed of a neural tube flanked by presomitic mesoderm that was sequentially segmented into somites. Periodic activation of the somite differentiation gene MESP2 coincided in space and time with anteriorly traveling segmentation clock waves in the presomitic mesoderm of the organoids, recapitulating key aspects of somitogenesis. Through timed perturbations of organoids, we demonstrated that FGF and WNT signaling play distinct roles in axial elongation and somitogenesis, and that the segmentation clock waves are driven by FGF signaling gradients. By generating and perturbing organoids that robustly recapitulate the architecture and dynamics of multiple axial tissues in human embryos, this work offers a means to dissect complex mechanisms underlying human embryogenesis.
These two very cool, related papers use machine learning & in vitro experiments to create a highly efficient & robust approach for developing human embryo organoids - enabling mechanistic analyses. They then use their system to uncover mechanisms of human embryogenesis: they show that WNT & FGF induce a signaling center of neuromesodermal progenitors that drives axial elongation, and that sequential segmentation of somites occurs via FGF signaling gradients (I'm not sure how much of this was already known from mouse studies...).