We are very excited about this work shedding light on long-standing questions in #devbio, #stemcell and #neuralcrest fields regarding regulation of cell heterogeneity, plasticity and #pluripotency.
@Stanford @ChemSysBio @ScienceMagazine
A twittorial... https://science.sciencemag.org/content/371/6529/eabb4776

Cell potency rapidly decreases during gastrulation and formation of the three germ layers each giving rise to specific lineages. However CNCC challenge this paradigm as they possess a superior developmental potential – broader than that of ectodermal germ layer of origin

We combined scRNA-seq of CNCC from from 4 to 10 somite stages of development corresponding to CNCC induction, delamination and first differentiation decisions, with the follow-up in vivo scRNA-seq validation, lineage tracing, loss-of-function and epigenomic profiling experiments

e first showed pre-migratory CNCC form distinct subpopulations with anterior-posterior information reflective of their site of origin in the neuroepithelium. However this positional information is rapidly erased with delaminating CNCC presenting a uniform molecular signature

We speculate formation a transcriptionally (and likely also functionally) equivalent population, allow CNCC to later adapt to environmental cues.
We hope this will reconcile the controversy of whether CNCC are heterogenous or homogenous at first

Next we identified a CNCC precursor population characterized by expression of canonical pluripotency transcription factors Oct4, Nanog, Klf4 and Sox2. Expression of these factors – in particular Oct4 and Nanog – is extremely dynamic along the AP axis of the embryo

scRNAseq analysis predicted that rather than being maintained from the epiblast, pluripotency factors are transiently reactivated in the prospective CNCC following head-folds formation. This was confirmed in vivo using FISH, in vivo GFP reporter

Furthermore in vivo lineage tracing confirmed Oct4 expressing cells gives rise to CNCC and craniofacial structures

Using mouse mutants, we demonstrated Oct4 is essential for facial mesenchyme specification and survival, directly linking this pluripotency factor with CNCC cellular potential expansion and reprogramming

We further showed that open chromatin landscapes of Oct4+ CNCC progenitors broadly resemble those of pluripotent epiblast stem cells, with additional features of priming for mesenchymal programs

These results demonstrate that CNCC precursors transiently reactivate pluripotency programs and suggest that these cells undergo a natural in vivo reprogramming event – at least partly mediated by Oct4 – that allows them to climb uphill on Waddington’s epigenetic landscape