Self-organization of stem cells during neural specification


The origin of cell type diversity in stem cell culture remains a key question in basic cell biology, disease modeling, and drug discovery. Human ES and iPS cell lines reflect the epiblast stage in early development where immediately prior to gastrulation, cell fates are spatially segregated by migration during an epithelial to mesenchymal transition in response to the organizing factor nodal. Similarly, cultured pluripotent cells self-organize into discrete domains that exhibit properties of lineage priming, or expression of gene expression modules that reflect terminally-differentiated cell fates of the early embryo. Applying spatial relationship analysis to this developmental system, we (1) establish a methodology that enables quantitative analysis of early embryonic development in an unconstrained monolayer cell culture, (2) demonstrate that individual cells are members of a developmental domain due to current local position, not historical identity, (3) establish that cell lines differ in their kinetics of domain formation and (4) use variable gene expression modules to demonstrate that stem cells share unique properties with donor brains from which they were derived.