Yesterday, I wandered around the poster session asking for favorite talks, and though my sample was only about 10 attendees, a few speakers’ names recurred. Much of this has been published or will soon be.
Magic marker everywhere
Hans Clevers has used the marker Lgr5 to definitively identify intestinal stem cells that can recapitulate this niche in a dish and likely the cell-of-origin for most intestinal cancer. Now he’s finding this marker in other organs: ductal cells in the stomach, plus pancreatic cells that have been stimulated to divide by injury.
What fish have for folks
Harvard’s Len Zon impressed folks with his story of how basic science in fish can lead to clinical trials in people. The molecule prostaglandin might just allow umbilical cord blood cells to be expanded, so more patients can receive transplants from those cells. ( Stem cell therapies the old-fashioned way)
iPS and ES consistently different
Kathrin Plath’s work characterizing consistent gene expression differences between ES and iPS cells gained high interest, and was just reported in Cell Stem Cell. The consensus now seems to be that iPS cells will be most ideal for some disease-study applications, ES cells for other disease-study applications. It sounds like the papers making these points are already waiting in the wings.
Where oh where can we get some good beta cells?
A series of three talks showed three ways to try to make beta cells, the type that degenerates in many types of diabetes. No one showed that their cells could rescue diabetic mice, and much of the work relied on markers rather than functional assays. Sarah Ferber from Sheba Medical Center in Israel described inserting genes for transcription factors into hepatocytes to make beta cells, similar to what Doug Melton showed last year with pancreas exocrine cells. (See Smash the (cell) state ) She thinks no single factor will be able to work magic, instead ideal combinations should be found. Harry Heimberg noticed that the cells proliferate within an injured pancreas express Ngn3, and then went on a beta cell progenitor hunt. The Ngn3 cells he subsequently identified seemed quite capable of becoming beta cells, but they don’t proliferate in culture, which makes the work seem a very interesting journey to a clinical dead end. He’s applying his procedures to look for other progenitors now. Finally, Harvard’s Doug Melton said that his goal was to make “bucketfuls rather than handfuls” of cells, and for that it’s best to start with embryonic stem cells. He represented cells as a series of stepping stones from ES cells to functioning beta cells, and then used chemical screening to identify small molecules that could make cell cultures jump between some steps quite efficiently. (See Embryonic stem cell differentiation: the right tweak at the right time He also had an ex vivo mouse embryo model that could test, over E7.5 to E9.5. Taking this work to clinical applications will mean finding a commercial partner.
Complex patterns from simple subroutines in the lung
Stanford’s Mark Krasnow showed gorgeous work tracking all of the 5,000 branching events in the developing lung, followed by a glimpse of molecular signaling pathways that, with a little tweaking, might help patients with asthma breathe easier.
The initial work meant dissecting mouse embryos at timepoints down to the minute as the lung formed. All these events and all that complexity comes down to just three types of branching events: bifurcating in a plane, bifurcating with a twist, and sprouting branches in a row. A series of just a few subroutines can recapitulate the process, but this really just leads to more questions. How does smooth muscle come to cover the airways? How does the pulmonary vasculature meet up with the airways?
The used lineage tracing to mark cells and found some surprises: everyone had assumed that muscle progenitors where in the stalks of branches, but they actually move down from the tips. And then there’s the question of where the endothelium lining blood vessels comes from: they don’t the mesenchyme of the developing airway as expected, nor do they bud off the arteries. Instead the progenitor cells are scattered everywhere, starting what Krasnow called “an unusual remodeling process” And in each branch the blood vessels’ smooth muscle coat has a distinct set of progenitors from those forming smooth muscle progenitors.
How is all this coordinated: the researchers mapped the signals being expressed in the tips of the branches and identified 21 ligands around each budding branch, along with 31 receptors, several of which are unknown. The also found distinct signaling pathways activated when prognitors are remaining in the niche, being recruited from the niche, or differentiating.
Now they are looking to see what happens as these processes are manipulated. And the end result, beside a basic understanding how beautiful, complex organs form, might be a new approach to asthma. Some therapies literally burn-off too-thick smooth muscle from the airways. Perhaps Krasnow’s work could lead to a less caustic route to the same result.