I am pleased to write this introduction to the new Journal of Cell Science Article Series on Stem Cells. Stem cell research is now regarded as one of the most exciting fields of biomedical research. However, its origins lie in several distinct research disciplines, including developmental biology, pathology and immunology. Developmental biologists have long been interested in how different cell types arise in the embryo, whereas a desire to understand how tissues are maintained in adulthood and how those processes fail in disease falls within the remit of pathologists. A key feature of adult tissues is cellular heterogeneity – the origin of diverse types of blood cell from a less-differentiated cell led immunologists to make major contributions to the field of stem cell research.
Stem cells can be defined as cells with extensive renewal capacity and the ability to generate daughter cells that undergo further differentiation. They have a number of different origins and properties. Adult stem cells generate the differentiated lineages that are appropriate for the tissue in which they reside and are unipotent or multipotent, depending on whether they give rise to one or multiple differentiated cell types. Stem cells cultured from pre-implantation mouse and human embryos are known as embryonic stem (ES) cells and are pluripotent: they have the ability to generate all the differentiated cells of the adult organism. Pluripotent stem cells can also be derived from the post-implantation epiblast of mouse embryos (epiSCs) and from primordial germ cells (EG cells), progenitors of adult gametes. Adult cells can be reprogrammed to a pluripotent state by the transfer of an adult nucleus into the cytoplasm of an oocyte, by fusion with a pluripotent cell or by conversion to induced pluripotent stem cells (iPS cells). The first iPS cells were generated by retrovirus-mediated transduction of mouse fibroblasts with Oct4, Sox2, KLF4 and Myc. iPS cells can also be generated from adult human cells, from a range of tissues and from cells of patients with specific diseases.
The reason why stem cell research is such an exciting field is that it not only offers the opportunity to understand fundamental mechanisms of self-renewal, differentiation and disease, but also because that knowledge can be applied to develop new treatments for a variety of diseases. Stem cell behaviour is governed both by intrinsic mechanisms, such as specific transcription factors, and by extrinsic signals from the local environment (i.e. microenvironment or niche). These are current areas of intense research and it is becoming clear that the interactions between stem cells and their niche and between intrinsic and extrinsic signals are reciprocal and dynamic. Another area of considerable interest is cellular heterogeneity, including the extent to which differences between individual cells are stochastic or represent stable differences in cell state. The practical importance of cellular heterogeneity is evident in recent studies of clonal evolution in cancers, such as leukaemias. A further area that is attracting considerable interest is in direct conversion of one cell type into another without the need to transition through the pluripotent state.
Alongside advances in fundamental stem cell research there are important developments to facilitate potential stem cell therapies. For instance, there is a considerable effort worldwide to bank embryonic and iPS cells of known provenance and to optimise protocols for generating differentiated cell types. In addition, stem cells from a variety of sources are being used to identify the genetic basis of disease and for new cell-based drug screens. If iPS cells are to be introduced into patients, safety is of paramount importance and, therefore, there is an ongoing effort to replace viral vectors with small molecules to induce the pluripotent state. Adult stem cells are being used increasingly to treat a variety of human conditions, and it is crucial that such treatments are only made available following well-controlled clinical trials. The advent of stem cell ‘tourism’, whereby desperate patients are subject to unproven stem cell therapies at great cost to their health and finances, is a serious cause for concern.
In some cases, stem cell research has led to major conceptual advances in understanding why existing disease treatments succeed or fail. This is illustrated in the case of cancer. The concept that cells in tumours are heterogeneous, with only some cells – the cancer stem cells or tumour-initiating cells – being capable of tumour maintenance or re-growth, is leading to the design of new types of combination therapy. It is also exciting to note how, at the interface between cell biology and bioengineering, new scaffolds are being developed for improved stem cell delivery or to encourage tissue repair by endogenous stem cells.
The series of articles that follows covers many of the topics that are most exciting in stem cell research. I hope that you will enjoy them and I thank the authors for making the series possible.