Revisiting LIF/GP۱۳۰/JAK/STAT۳ Signalling in Human Pluripotent Stem Cells

Pluripotent stem cells (PSCs) can be derived and expandedin culture from the epiblast of the mammalian blastocyst. Inmice, PSCs are called embryonic stem cells (ESCs). Inhibitionof their differentiation and promotion of self-renewal arecontrolled by the LIF/GP۱۳۰/JAK/STAT۳ signalling pathwayand do not require MAPK activity, which epitomizes the naïve(or ground) state of pluripotency. Although human PSCsare generated from the epiblast of the blastocyst similar to theirrodent counterpart, they rely on FGF۲ and Activin signallingfor inhibition of differentiation, a property that epitomizes theprimed state of pluripotency. All attempts to propagate humanPSC lines using the culture conditions previously established tocapture the naïve (or ground) state of pluripotency as defined inmice have been unsuccessful.We sought to reactivate the LIF/GP۱۳۰/JAK/STAT۳ signallingpathway in human PSCs to know if this would sustain self renewal and inhibit differentiation as previously described inmice. Human PSCs fail to activate STAT۳ target genes after LIFstimulation, LIF-independent GP۱۳۰ dimerization, or GP۱۳۰/JAK-independent activation of STAT۳, indicating human PSCsare blind to STAT۳ activity. However, combinations of theabove, such as the concomitant activation of the GP۱۳۰ receptorand overexpression of a GP۱۳۰/JAK-independent STAT۳,activate STAT۳-target genes and inhibit differentiation. Thetransition from a FGF۲- to a JAK/STAT۳-dependent mode ofself-renewal is accompanied by a transcriptome reconfigurationand by an alteration of cell-cycle parameters, consistent witha conversion to the naïve-like state of pluripotency. I proposethat a synergy between STAT۳ and one or several co-factorsdownstream of GP۱۳۰ is necessary to sustain self-renewal ofhuman PSCs.