In an important scientific breakthrough in regenerative medicine, researchers at A*STAR’s Genome Institute of Singapore (GIS) have successfully converted human embryonic stem cells (hESCs) cultured in the laboratory to a state that is closer to the cells found in the human blastocyst. This means that scientists are one step closer to cultivating stem cells for research and potential therapeutic purposes, as well as understanding the processes of early human development. These findings are published in the current issue of the prestigious science journal Cell Stem Cell.
Pluripotent stem cells such as hESCs and induced pluripotent stem cells (iPSCs) have the remarkable ability to differentiate into various cell types of the adult body while proliferating continuously in culture. In the field of regenerative medicine, these cells are potentially a limitless resource to generate cells of different body parts such as the eye, liver, brain, kidney and pancreas to treat degenerative diseases or replace of worn out organs. Pluripotency is the essential property of the cells of the blastocyst in the early stages of human development. However, when cultured in the laboratory, these cells adopt molecular differences, which limit their use in therapeutic applications or disease modeling.
Using previously established hESCs, the researchers screened for culture conditions that could induce a stable change of cell state. They found that the use of a specific combination of small molecules and growth factors, termed 3iL, converted hESCs to a state that resembled cells within the native blastocysts.
Ref: Induction of a Human Pluripotent State with Distinct Regulatory Circuitry that Resembles Preimplantation Epiblast. Cell Stem Cell (5 December 2013) | DOI: 10.1016/j.stem.2013.11.015 | PDF (Open Access)
Human embryonic stem cells (hESCs) are derived from the inner cell mass of the blastocyst. Despite sharing the common property of pluripotency, hESCs are notably distinct from epiblast cells of the preimplantation blastocyst. Here we use a combination of three small-molecule inhibitors to sustain hESCs in a LIF signaling-dependent hESC state (3iL hESCs) with elevated expression of NANOG and epiblast-enriched genes such as KLF4, DPPA3, and TBX3. Genome-wide transcriptome analysis confirms that the expression signature of 3iL hESCs shares similarities with native preimplantation epiblast cells. We also show that 3iL hESCs have a distinct epigenetic landscape, characterized by derepression of preimplantation epiblast genes. Using genome-wide binding profiles of NANOG and OCT4, we identify enhancers that contribute to rewiring of the regulatory circuitry. In summary, our study identifies a distinct hESC state with defined regulatory circuitry that will facilitate future analysis of human preimplantation embryogenesis and pluripotency.