The ‘precarious balance’ model of pluripotency proposed by Loh and Lim
Embryonic stem cells (ESCs) are characterized by their ability to differentiate into almost all cell types in the body. The conventional model holds that this ‘pluripotency’ represents an inherently stable ground state in which ESCs remain undifferentiated owing to a protective shield of suppressive pluripotency transcription factors that block differentiation. According to this model, ESCs differentiate into functional cell types, such as muscle cells or neurons, only when the expression of certain pluripotency factors is switched off. However, little has been known about the mechanisms underlying the vast development potential of ESCs.
Kyle Loh and Bing Lim at the A*STAR Genome Institute of Singapore have now proposed a new theory to explain the unrestricted multi-lineage potential of ESCs. Based on their reinterpretation of existing findings, the researchers suggest that pluripotency factors act as ‘lineage specifiers’ that direct commitment to specific cell lineages, while prohibiting concomitant differentiation into mutually exclusive lineages (see image).
“We proposed that individual pluripotency factors bestow ESCs with the ability to differentiate into particular cell types, and that the concomitant expression of multiple lineage specifiers within pluripotent cells enables differentiation into every fetal lineage. We are the first to posit an explanation for this remarkable ability,” explains Loh.
According to Loh and Lim’s model, pluripotent cells exist in a precarious condition in which they are engaged in continuous competition with rival pluripotency factors to specify differentiation along mutually exclusive lineages. Thus, for example, if a particular set of pluripotency factors is expressed over and above another, ESCs will differentiate into a neuronal lineage, rather than, say, a muscle lineage.
In support of their theory, the researchers cited examples in which experimental overexpression of specific pluripotency factors induces ESC differentiation. “Such findings are difficult to reconcile with existing theory, which predicts that overexpression of individual pluripotency factors should prohibit ESC differentiation,” explains Loh.
“We draw the analogy that pluripotent cells exist at the summit of the proverbial mountain of developmental potential,” says Loh. “Understanding how such a vast range of lineage choices is made available to ESCs will have important implications for their application in biotechnology and stem cell therapy.”
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.
