The Origins of Human Embryonic Stem Cells: A Biological Conundrum

Human inner cell mass (ICM) cells isolated from in vitro fertilized blastocysts are the progenitor cells used to establish in vitro stable human embryonic stem cells (hESCs) which are pluripotent and self-renew indefinitely. This long-term perpetuation of hESCs in the undifferentiated state is thought to be an in vitro adaptation of the ICM cells. To investigate at the molecular level how hESCs acquired their unique properties, transcriptional profiles of isolated ICM cells and undifferentiated hESCs were compared. We identified 33 genes enriched in the ICM compared to the trophectoderm and hESCs. These genes are involved in signaling cascades (SEMA7A and MAP3K10), cell proliferation (CUZD1 and MS4A7) and chromatin remodeling (H1FOO and HRMT1L4). Furthermore, primordial germ cell-specific genes (SGCA and TEX11) were detected as expressed in the ICM cells and not hESCs. We propose that the transcriptional differences observed between ICM cells and hESCs might be accounted for by adaptive reprogramming events induced by the in vitro culture conditions which are distinct from that of in vitro fertilized blastocysts. hESCs are a distinct cell type lacking in the human embryo but, nonetheless, resemble the ICM in their ability to differentiate into cells representative of the endodermal, ectodermal and mesodermal cell lineages.