A molecular and mechanistic understanding of the control of the fate of stem cells is a priority for fundamental and translational scientists alike. How cellular diversity is created is one of the most fundamental questions in biology. Once development is complete, homeostasis requires the constant activity of stem cells to renew and replace terminally differentiated or senescent cells. Major break-throughs have sparked stem cell research. In 1981, embryonic stem cells were derived from early mouse embryos. In 1998, human embryos were created for reproductive purposes through in vitro fertilization procedures. In 2006, specialized adult cells were reprogrammed genetically to induce pluripotent stem cells.
The utmost distinctive characteristic of stem cells is their renewing properties through cell division, even sometimes after dormant, inactive periods. Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. The inner cells of the blastocyst in the early embryo give rise to the entire body of the organism. Stem cells in many tissues divide without limit to restore the cellular pool. When a stem cell divides, each new cell has the potential either to remain a stem cell or to become another type of cell with a more specialized function. In some adult tissues, distinct populations of stem cells replace cells that are eliminated due to physiological or pathological processes.
The ability of stem cells to be induced to become tissue- or organ-specific cells with special functions varies and is controlled by particular conditions. Our understanding of the molecular mechanisms that control cell fate decisions is still in its infancy, although the role of several signaling, transcriptional, and epigenetic pathways have been unveiled in the last decades. Each of these processes is highly intertwined with proliferation pathways, such that defects are commonly associated with tumorigenesis. The high level of controversy that exists in the field reflects on the high level of complexity that is at the core of these organismal, cellular, and molecular biological systems.
Embryonic stem cells have the potential to give rise to any cell types in the human body, raising exciting prospects for biomedical research and for regenerative medicine. Given their unique regenerative properties, these cells have spun the expansion of research studies that aim to understand the mechanistic events that control stem cell regenerative process to the design of cellular or pharmacological therapeutic approaches to restore or manipulate the pool of stem cells. The remarkable plasticity of stem cells makes them extremely appealing for biomedical research, but at the same time, brings challenges due to the high level of complexity of molecular signaling, genetic, and epigenetic pathways involved in the control of their development. Given that stem cells are difficult to manipulate, therapeutic applications to influence their environments may be a more feasible alternative approach.
Although our knowledge on cellular and molecular characteristics of stem cells grew in the last decades, how stem cell fate is mechanistically regulated at the molecular level remains to be clarified. The Journal of Molecular Biology is presenting a series of four reviews and two original research articles that highlight important areas of research in the field.
Chen and colleague review the different regulatory networks that differentiate mammalian embryonic stem cells. Among the most critical extrinsic ones are the transforming growth factor-β/Activin and the Wnt signaling pathways. The authors discuss the dynamics changes in the landscape of histone modifications and the cross-talk between extrinsic and epigenetic mechanisms [1].
Chuong and colleagues focus their review on several examples of the regulation of stem cells in hair follicles by macro-environmental signals: intradermal adipose tissue, innate immune system, sex hormones, aging, circadian rhythm, and seasonal rhythms [2].
Gilbert and colleagues discuss evidence showing that the dynamic changes in the biophysical properties of the skeletal muscle (stiffness, stretch, and shear forces) drive the activation and silencing of signal transduction pathways responsible for satellite cell fate decisions [3].
Prehoda and colleague review in diverse systems evidence that the atypical Protein Kinase C is a key regulator of progenitor and stem cell fate decisions in metazoans. Progenitor cells are distinct from stem cells as the former have taken steps toward differentiation and do not have the property to generate any cell lineage. The authors discuss the molecular pathways that control this kinase and those that respond to changes in its catalytic activity [4].
Teitell and colleagues demonstrate in an original research article the molecular mechanisms involving mitochondrial Bak that induces apoptosis of human pluripotent stem cells with unrepaired genome alterations and Mdm2 that mediates rapid p53 degradation in pluripotent but not differentiated stem cells [5].
Edenhofer and colleagues explore novel reprogramming pathways for enhancing the developmental plasticity of neural stem cells in culture. The authors dedifferentiate developmentally restricted radial glia-type neural stem cells into a more plastic neuroepithelial state using a transcription-factor-based cell fate conversion strategy (POU domain transcription factor Brn2 together with c-Myc) combined with the use of pharmacological compounds [6].
References
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