The well charted course for most embryonic stem cells is to completely differentiate into dedicated cell types that form the bulk and mass of organs and organelles. The other more uncommon course and perhaps viewed by many as Nature's back up plan is the conversion of embryonic stem cells into pluripotent cells that harness their inherent potential to differentiate into different organ types or tissue types.
In effect, pluripotent stem cells, apart from being faithful replicators of organ fate, have doubled up as the cause for the burgeoning stem cell industry that thrives heavily on their contribution to regenerative medicine, bone marrow transplantation and cord cell banking. While, stem cells continue to fascinate scientists and clinicians alike about their potential therapeutic potential,the underpinnings of the fundamental basis that determines the fate of stem cells to choose between self renewal or priming for differentiation, has been a dilemma that has left the scientific community perplexed for a long while.
Ostensibly, the first breakthrough in answering the dillema came from Ian Chambers' research group at the University of Edinburgh in the avatar of Nanog, as the master regulator that determines the fate of pluripotent stem cells;it answered the questions only partially. Inputs surrounding the mechanics of activating the Nanog gene and the ability of pluripotent stem cells to continually renew themselves remained unanswered,which has perhaps been rate limiting in developing susccessful stem cell therapeutics.
Working towards addressing this very challenge,a research group based at the University of California, Berkeley, has announced a breakthrough that signals a significant yet hitherto unlikely interaction between the DNA excision repair system and a set of transcriptional coactivators, that together, orchestrate the activation of Nanog in conferring embryonic stem cells with the quality of pluripotency.
Published in the latest issue of Cell, the research built its case on the basis of previous studies that had demonstrated a strong role for Oct4 and Sox 2 that serve as coactivators or transcription factors that support the activity of the Nanog transcription factor in endowing pluripotent behaviour in stem cells.Initial genetic loss of function studies on the popular HeLa tumor cell line, revealed that despite the repression of the Oct4,Sox2 function, Nanog continued to influence the fate of stem cells towards pluripotency.
The observation leads the team to suspect the influence of more players than initially suspected, in influencing pluripotency. In an attempt to explore further, the team developed an elegant methodology wherein the total protein complex was isolated from pluripotent stem cells and an invitro transcription factor assembly analysis was conducted.The protein complex however, gave way to a an unexpected proteinc that belong to the mammalian nucleotide excision repair pathway called the XCC, which when suppressed, led to arrest of the Nanog function hence stalling the differentiation and self renewal potential of pluripotent stem cells.
The study, as it were,clears much cloud surrounding the fundamental principles governing cell differentiation and potentially opens up avenues for developing customized therapeutics through effective reprogramming of the coactivator proteins to ensure stability of therapeutic pluripotent stem cells and thereby elicit a sustainable cure for complex diseases that warrant targeted therapies.