Growth factor signal interpretation in stem cells and the early embryo.

A fundamental goal of biology is to understand the molecular basis of cell identity, and how an identity can be maintained or acquired in vivo and also in vitro, and to convert this eventually into medical therapy. The progressive changes from the totipotent zygote to pluripotent stem cells in the embryo and subsequently germ-layer and tissue specific stem cells (Fig.1, where a mouse embryo is shown), and ultimately the generation of all mature cells and perfectly shaped tissues and organs, have been studied by embryologists in mice (and mutant mice) and different types of stem cells derived from these. Progressive loss of potency and acquisition of lineage specification are regulated at the epigenetic, transcriptional and posttranscriptional levels, and are mediated by growth factors, chiefly members of the Wnt, Tgfbeta (Nodal and Bmp), Hedgehog (Hh) and Fgf families and their receptors, and Notch receptor and its ligands. These ligand-receptor interactions influence cell responses via their signal transduction pathways that converge on specific targets, including proteins and genes encoding transcription factors (TFs), whose activity and expression is then modified [1]. Growth factors thus steer cell fate and determination through combining their extrinsic control with an intrinsic one that emanates from key TFs in the target cell. Stem cell researchers also study self-renewal, maintenance and gradual loss of potency, which accompanies differentiation of embryonic stem cells (ESCs), as well as tissue-specific stem cells. Of note, recent studies have shown that the reverse process, i.e. gain of potency, by re-programming terminally differentiated cells into pluripotent cells (iPS cells) by transfection or transduction of combinations of key TFs, alone or in combination with chemicals [2-8]. Thus, human pluripotent stem cells can be isolated from embryos or created from differentiated cells, and tissue-specific stem cells can be isolated from multiple tissues. If efficient methods for differentiation could be developed, progeny of all such stem cells may be suitable for therapy. In addition, if the molecular mechanisms responsible for such differentiation are better understood, it may also be possible to identify key signaling events that are drugable, such that differentiation of endogenous pool of tissue-specific stem cells can be improved or enhanced as therapy. In this GOA, we start from the conviction that, for future translation, insights gained from studies in the whole-embryo setting will be of crucial importance to better understand differentiated cells and generate them from stem cells, and vice versa. So, indepth insight in the molecular codes of growth factor and TF action in embryos, and in differentiation and de-differentiation processes, will eventually be crucial to explain and diagnose many diseases, and treat these appropriately, including with cell-based therapy.

Keywords:Growth factor signal, stem cells, early embryo

Disciplines:Laboratory medicine, Palliative care and end-of-life care, Regenerative medicine, Other basic sciences, Other health sciences, Nursing, Other paramedical sciences, Other translational sciences, Other medical and health sciences