Stem cells: therapeutic prospects for diabetes mellitus
Type 1 diabetes mellitus has received much attention recently as a potential target for the emerging science of stem cell medicine. Advances in islet transplantation procedures now mean that patients with the disease can be cured by transplantation of primary human islets of Langerhans. A major drawback in this therapy is the availability of donor islets, and the search for substitute transplant tissues has intensified in the last few years. This review lecture will investigate the essential requirements of a material designed as a replacement β-cell and will look at the potential sources of such replacements. Early work using mouse embryonic stem (mES) cells demonstrated that, either by genetic manipulation, or by allowing the formation of “embryoid bodies (EBs), it was possible to generate cells that expressed some elements of a β-cell phenotype. Since the ultimate goal is to transfer these technologies to human cells to generate a transplantable tissue, we have avoided the genetic manipulation of mES cells and instead our mES cell work has focused on reducing the unregulated differentiation inherent in the EB stage of the previously described strategies. Although more difficult to work with, reports have suggested that human ES (hES) cells can undergo spontaneous differentiation into insulin-expressing cells, albeit at very low frequency. We have confirmed these data using both a commercially available hES cell line and a hES cell line generated at Kings College London and our work suggests that these cells need to be maintained at high density or in three dimensional clusters for the appropriate genes to be expressed. A number of reports have described the therapeutic potential of multipotent adult stem/progenitor cells, from a range of tissues including the pancreas, intestine, liver, bone marrow and brain. In support of this, we have demonstrated that neural stem cells, isolated from the foetal rat forebrain, display significant potential for the generation of glucose-sensitive insulin-expressing cells. More recently, the capability of hES cells generated by somatic cell nuclear transfer and some adult stem cell populations, such as bone marrow-derived stem cells, to offer autologous transplant material has highlighted the clinical relevance of deriving strategies for the effective generation of insulin expressing cells.
The lecture will describe the work I have undertaken at Kings College London using stem cell lines from multiple sources including neural stem cells (NSCs) and ES cells of mouse and human origin.