stem cells – Drug Discovery Opinion

GSK-3 – Master Controller of Neural Stem Cells

GSK-3 (glycogen synthase kinase-3) is a serine-threonine kinase that consists of two family members in mammals, α and β, which share 98% sequence identity in their kinase domains. The β-isoform has recently been identified as a mediator of neurogenesis under the control of DISC1, a protein encoded by a gene implicated in schizophrenia susceptibility. GSK-3 has also been shown to be involved in regulation of embryonic stem cell self-renewal – GSK3 inhibitors help in maintenance of pluripotency.

A new study from researchers at the University of North Carolina at Chapel Hill School of Medicine has now shown that GSK-3 is a key regulator of neural stem cell proliferation and differentiation. Neural stem cells progress through different stages – neural epithelial cells, radial progenitor cells and intermediate neural precursors – and radial progenitor cells are particularly important because they are thought to provide the majority of the neurons of the developing brain and to give rise to all the cellular elements of the brain. The researchers used a conditional knockout in a mouse model, deleting both isoforms of GSK-3 during the radial progenitor phase of development. This resulted in locking the radial progenitor cells in a proliferative state, with no generation of mature neurons. The next step is to determine whether switching GSK-3 back on can stimulate differentiation, leading to an increased number of mature neurons. The researchers suggest that understanding the role of GSK-3 in neurogenesis could have implications for patients with neuropsychiatric conditions such as schizophrenia, depression and bipolar disorder.

The study is published in the journal Nature Neuroscience.

GSK-3 Inhibitors Help Maintain Pluripotency

Although the use of embryonic stem cells is controversial and hotly debated from both sides, many researchers believe that these cells offer the promise of revolutionary treatments for a wide variety of diseases and injuries, including spinal cord injuries and degenerative diseases.

Embryonic stem cells are derived from the inner cell mass of an early stage embryo and are pluripotent, meaning that they are able to differentiate into any of the more than 200 cell types that make up the human body. For their full potential to be realised, it is important to maintain this pluripotency whilst growing them in cell culture. Glycogen synthase kinase 3 (GSK-3) had previously been implicated as a regulator of both self-renewal and differentiation, and a study published in the journal Chemistry and Biology now clarifies the role of GSK-3 in murine embryonic stem cell development by showing that inhibitors of GSK-3 enhance self-renewal in the presence of serum and leukaemia inhibitory factor. The authors propose that, by inhibiting GSK-3 activity in the appropriate cell culture environment, it will be possible to more easily obtain large numbers of undifferentiated, pluripotent, cells for medical use. Once the inhibitor is removed from the cell culture medium, it is possible to induce the stem cells to differentiate into the chosen type of specialised cells.
gsk-3 inhibitor

Boost for Stem Cells

Mesenchymal stem cells Mesenchymal stem cells can differentiate into a variety of cells including osteoblasts and chondrocytes A new discovery increases the likelihood that treatments could eventually boost specific subtypes of stem cells, and promote self healing following injury or disease. In response to tissue injury or disease, progenitor cells are mobilised from bone marrow into the tissues and contribute to tissue repair and regeneration. Different subpopulations of progenitor cells are recruited depending on the type and site of disease or tissue injury. Although it is becoming apparent that specific types of progenitor cells could be used to treat a variety of diseases, there are practical and technical difficulties in harvesting, isolation, ex vivo expansion, and delivery of these cells. An alternative strategy would be to directly stimulate the mobilisation of specific populations of stem cells from the bone marrow into the circulation. Scientists at Imperial College, London, have shown that the mobilisation of progenitor cell subsets can be differentially regulated by growth factors that affect their retention in bone marrow and cell-cycle status. Treatment of mice with granulocyte colony-stimulating factor (G-CSF) followed by the CXCR4 antagonist, Mozobil™ (AMD3100), caused maximal mobilisation of hematopoietic stem cells (HPCs) and neutrophils. On the other hand, treatment with vascular endothelial growth factor (VEGF) followed by Mozobil™ maximally stimulated mobilisation of endothelial progenitor cells (EPCs) and stromal progenitor cells (SPCs). By showing that different factors and molecular mechanisms regulate the mobilisation of discrete populations of progenitor cells from the bone marrow, the study has far reaching implications for regenerative medicine. Although it is not yet clear whether such an approach would, for example, speed cardiac repair following myocardial infarction or promote bone healing after a fracture, the ability to selectively mobilise different stem cell populations will enable further research in these areas. The study is published in full in the January 9th issue of Cell Stem Cell.