Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies.

The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new products.

The self-renewal of mouse embryonic stem cells is regulated by cell-substratum adhesion and cell spreading.

Mouse embryonic stem cells (mESCs) undergo self-renewal in the presence of the cytokine, leukaemia inhibitory factor (LIF). Following LIF withdrawal, mESCs differentiate, and this is accompanied by an increase in cell-substratum adhesion and cell spreading. The purpose of this study was to investigate the relationship between cell spreading and mESC differentiation. Using E14 and R1 mESC lines, we have restricted cell spreading in the absence of LIF by either culturing mESCs on chemically defined, weakly adhesive biomaterial substrates, or by manipulating the cytoskeleton. We demonstrate that by restricting the degree of spreading by either method, mESCs can be maintained in an undifferentiated and pluripotent state. Under these conditions, self-renewal occurs without the need for LIF and is independent of nuclear translocation of tyrosine-phosphorylated STAT3 or ß-catenin, which have previously been implicated in self-renewal. We also demonstrate that the effect of restricted cell spreading on mESC self-renewal is not mediated by increased intercellular adhesion, as evidenced by the observations that inhibition of mESC adhesion using a function blocking anti E-cadherin antibody or siRNA do not promote differentiation. These results show that mESC spreading and differentiation are regulated both by LIF and by cell-substratum adhesion, consistent with the hypothesis that cell spreading is the common intermediate step in the regulation of mESC differentiation by either LIF or cell-substratum adhesion.