Search

The zinc finger transcription factor GATA-2 plays a fundamental role in generating hematopoietic stem-cells in mammalian development. Less well defined is whether GATA-2 participates in adult stem-cell regulation, an issue we addressed using GATA-2heterozygote mice that express reduced levels of GATA-2 in hematopoietic cells. While GATA-2+/–mice demonstrated decreases in some colony-forming progenitors, the most prominent changes were observed within the stem-cell compartment. Heterozygote bone marrow had a lower abundance of Lin–c-kit+Sca-1+CD34–cells and performed poorly in competitive transplantation and quantitative week-5 cobblestone area–forming cell (CAFC) assays. Furthermore, a stem-cell–enriched population from GATA1+/–marrow was more quiescent and exhibited a greater frequency of apoptotic cells associated with decreased expression of the antiapoptotic gene Bcl-xL. Yet the self-renewal potential of the +/– stem-cell compartment, as judged by serial transplantations, was unchanged. These data indicate compromised primitive cell proliferation and survival in the setting of a lower GATA-2gene dose without a change in the differentiation or self-renewal capacity of the stem-cells that remain. Thus, GATA-2 dose regulates adult stem-cell homeostasis by affecting select aspects of stem cell function.

In metazoans, adult, tissue-specific stem cells function to naturally replace and regenerate components of organ systems during life. The restorative power of adult stem cells has been best exploited clinically in bone marrow transplantation to treat blood cancers and other disorders. With the discovery and characterisation of other adult stem cell types and pluripotent stem cells capable of generating all tissues in the body, it has been postulated that stem cells may be of utility in replacing other tissues which have stopped functioning due to age or disease. However, the potential application of stem cells to regenerative medicine is vast and more multi-faceted than simply furnishing replacement tissue in failing organ systems. In this minithematic issue of Current Drug Delivery, we explore these other applications focusing on current knowledge about the regulation of stem cells, its implications for pathogenesis in cancer and cell therapy and how stem cells may be used as drug delivery agents and as tools in disease modelling and drug discovery. Adult stem cell function during homeostasis and in response to periods of physiological demand relies on strict intrinsic regulation interwoven with complex extrinsic signals emanating from the micro-environment (or ‘niche’). That proper adult stem cell function in vivo is dependent on its niche was the concept first invoked in the blood system in the 1970s and is an idea that has gained considerable traction in this and other tissue systems more recently. The overall complexity of adult stem cell niches is gradually being understood at the level of cellular constituents and molecular pathways controlling their behaviour. In addition to its purely supportive role as a habitat for the stem cell, it is responsible for secreting growth factors and other regulatory proteins that extrinsically regulate stem cell functionality. Crawford and colleagues review the role of pigment epitheliumderived factor (PEDF), a critical regulator of neural stem cell self-renewal in the neural stem cell niche. The authors explore the potential therapeutic role of PEDF where its opposing positive effect on stem cell behaviour and powerful anti-angiogenic effect on cancers make it possible for it to operate as a selective drug in cancer while sparing or possibly boosting normal tissue function through harnessing endogenous stem cell function. It has also become increasingly clear how crucial the stem cell-niche collaboration is to the maintenance of normal tissue function: in the blood system the potentially dire consequences of disturbing particular constituents of the niche are evident in decreased stem cell function and the emergence of pre-cancerous and cancerous conditions in mouse models and select clinical syndromes. The niche may also provide a sanctuary that protects already existent cancer from the effects of treatment (e.g. chemotherapy), and enables eventual disease relapse. Bartos and Dubielecka-Szczerba explore how one potential component of the niche - actin cytoskeleton- is impacted by the Bcr-abl oncogene in chronic myeloid leukaemia, leading to drug and therapy resistance. Pluripotent stem cells, derived from the embryo (embryonic stem cells) or by reprogramming somatic cells to an embryonic state (induced pluripotent stem cells), and adult stem cells may impact cellular therapy in two distinct ways. As alluded to, they may directly replace damaged tissues in organ transplantation related strategies (see review by Stewart for examples using pluripotent stem cell derived tissue). Less well established but becoming more appreciated is that stem cells can function and act as drug delivery modalities, facilitating tissue replacement without formally integrating or replacing tissue. A case in point is mesenchymal stem/stromal cells (MSCs), which as English and colleagues discuss, have potent immune modulatory function that could be deployed to facilitate acceptance of allogeneic organ transplantation or to ameliorate graft versus host disease, a potentially fatal side-effect of allogeneic bone marrow transplantation (for another example, see Falanga and colleagues review of the use of MSCs to treat chronic wounds). Shinya Yamanaka was awarded the Nobel Prize in Physiology and Medicine in 2012 for discovering induced pluripotent stem cells (iPSCs), underscoring their potential to revolutionise therapies for a plethora of debilitating and fatal diseases via cell replacement therapy or drug discovery. For example, the capacity to make iPSCs from a somatic cell of a patient afflicted with a given disease offers an unprecedented opportunity to peer into the evolution of that disease by essentially rewinding its history in vitro and modelling the earliest pathological steps associated with it, with an ultimate view of identifying drug targets for treatment. Stewart reviews and explains progress made to date with disease specific iPSCs in this context set against a historical perspective of the pluripotent stem cell biology field. Finally, translating the potential of pluripotent stem cell derived tissue or adult stem cells (e.g. MSCs) into both safe and effective clinical therapies in any setting involving administration of cellular products requires adherence to Good Manufacturing Practice (GMP) supervised by the Food and Drug Administration (FDA) regulatory framework in the United States and by the European Medicines Agency (EMA) in Europe. Falanga and colleagues outline the laborious yet essential strategy required to establish a GMP lab for these purposes and describe their experience with using the laboratory to manipulate MSCs that will encourage chronic wound healing.