SPECISTEM

In the perspective of cell therapy or drug design, generation of a specific cell progenitor from Human embryonic stem (HES) cells or from Induced pluripotent stem (iPS) cells remains a challenge. Maintenance of pluripotency of ES or iPS cells requires Oct4 and Sox2 which in conjunction with Nanog trigger a specific transcriptional programme. Interestingly, we uncovered in HES cells that Oct-4, when upregulated (by cell stimulation with BMP2 or nucleofection of the cDNA) acts in combination with Sox17 an endodermal marker to switch on through a paracrine effect a genetic cell differentiation programme toward the cardiogenic lineage. We hypothesize that identification of both gene promoters and miRNAs, targets of Oct-4/Sox17 duo, as well as deciphering the epigenetic regulation of the Oct-4/Sox17 network (i.e., histone marks overlaying Sox2 and Sox17 promoters) in both HES and iPS cells will allow to secure a population of highly proliferative cardiac progenitors. To envision the use of early cardiac progenitors for drug screening, and cell therapy, we will search for molecules which activate the Oct-4/Sox17 network, and induce proliferation of early cardiac progenitors using High Throughput Screening and the NIH library of small compounds. The outcome of the project carried out with a US partner (HTS) and a Bioinformatics laboratory in Singapore should also provide crucial information to improve the generation and better evaluate the differentiation potential of iPS.