Cellular population dynamics shape the route to human pluripotency

Human cellular reprogramming to induced pluripotency is still an inefficient process and this has long hindered the study of the role of critical intermediate stages. We take advantage of high efficiency reprogramming in microfluidics and temporal multi-omics to identify and resolve distinct sub-populations and their interactions. The combination of secretome analysis and single-cell transcriptomics shows functional extrinsic pathways of protein communication between reprogramming sub-populations and the re-shaping of a permissive extracellular environment. We pinpointed the HGF/MET/STAT3 axis as a potent enhancer of reprogramming, which acts via HGF accumulation within the confined system of microfluidics, and in conventional dishes needs to be supplied exogenously to enhance efficiency. Our data integrate the notion of human cellular reprogramming as a transcription factor-driven process with the concept that it is deeply dependent on extracellular context and cell population determinants.