SOX2, OCT3/4 and NANOG expression and cellular plasticity in rare human somatic cells requires CD73.
We previously identified cell surface markers associated with repression of p16(INK4a)/cyclin-dependent kinase inhibitor 2A(CDKN2A), a critical determinant in the acquisition of a state in which cells can choose various fates, i.e. a "plastic" state. These cell surface markers allowed us to isolate rare cells from healthy human breast tissue that exhibit extensive lineage plasticity. We referred to these cells as "Endogenous Plastic Somatic (ePS) cells". These cells express canonical plasticity markers, OCT3/4, SOX2, and NANOG, at levels similar to those measured in human embryonic stem cells and to acquire a plastic state sensitive to environmental programming. However, in contrast to other cells that express OCT3/4, SOX2, and NANOG, ePS cells are mortal, express low telomerase activity, expand for a finite number of population doublings, and maintain a diploid karyotype before arresting in G1. In this more recent study, we visualized ePS cells in breast tissue sections. We also characterized ePS cells in a non-plastic (latent) state in which they do not express plasticity markers OCT3/4, SOX2, and NANOG and in a plastic state in which they express these plasticity markers. Moreover, we identified the signaling pathways required for the acquisition of plasticity markers OCT3/4, SOX2, and NANOG in latent ePS cells.
Endogenous Plastic Somatic (ePS) cells isolated from adult human tissues exhibit extensive lineage plasticity in vitro and in vivo. Here we visualize these rare ePS cells in a latent state, i.e. lacking SOX2, OCT3/4 and NANOG (SON) expression, in non-diseased breast specimens through immunohistochemical analysis of previously identified ePS-specific biomarkers (CD73(+), EpCAM(+) and CD90(-)). We also report a novel mechanism by which these latent ePS cells acquire SON expression and plasticity in vitro. Four extracellular factors are necessary for the acquisition of SON expression and lineage plasticity in ePS cells: adenosine (which is produced by the 5' ecto-nucleotidase CD73 and activates in turn the PKA-dependent IL6/STAT3 pathway through the adenosine receptor ADORA2b), IL6, FGF2 and ACTIVIN A. Blocking any pathway component renders ePS cells incapable of SON expression and lineage plasticity. Notably, hESCs do not use adenosine or IL6 nor they express CD73 or ADORA2b and inhibition of adenosine signaling does not ablate their plasticity. Therefore, the data presented here delineate novel circuitry and physiological signals for accessing SON expression in rare, undifferentiated human cells.