Derivation of Induced Pluripotent Stem Cells from Somatic Cells Donated by Patients with Neurological Diseases for the Study of the Pathogenesis of the Disorders and Development of Novel Therapies

The derivation of human iPS cells (1-5) open new avenues to model human diseases since it may now be possible to develop iPS cells from the fibroblasts or other somatic cells of patients with various conditions. These iPS cells may be directed to differentiate into the cells which are affected in specific conditions. Abnormalities in the development of the affected cells as well as altered survival or function of the cells may be studied. Thus iPS cells may serve as an invaluable model for the study of the pathogenesis of human diseases and may also serve for the development of new drugs, and high throughput screening of molecules for toxic or therapeutic effects.

In addition to the great potential of iPS cells for disease modelling and transplantation therapy, the cells may have broad applications in basic research in various areas such as reprogramming, basic development and others.

At present, it is still unclear whether the properties of iPS cells are identical to those of hESCs. Initial data suggest that human iPS cells are indeed similar to hESCs in their phenotype, epigenetic status of pluripotent self-specific genes, telomerase activity, gene expression profile and in their capability to differentiate into progeny of the three germ layers both in vitro and in vivo in teratomas (2, 3, 5). In the mouse system, directed differentiation of iPS cells into bone marrow repopulating hematopoietic stem cells and functional dopaminergic neurons was demonstrated (6, 7). However, incomplete silencing of the constitutive expression of the transcription factors that were used to induce reprogramming can probably interfere with differentiation (1). Further studies are required to confirm that the developmental potential and biological properties of iPS cells are identical to hESC.

Currently, retroviral vectors are most commonly used to introduce and express the transgenes which reprogram the somatic nucleus (1-5). The use of retroviral vectors, which integrate into the host cell genome, may cause hazardous insertion mutagenesis. Moreover, the use of potentially oncogenic transcription factors, such as c-Myc, significantly limits the clinical use of human iPS cells for future cell therapy. However, successful derivation of iPS cells was demonstrated without the forced expression of c-Myc. The decreased efficiency of reprogramming, in the absence of overexpressed c-Myc, may be improved by molecules which act via epigenetic mechanisms. Moreover, successful derivation of iPS cells was recently reported with the use of non-integrating adeno viral vectors or repeated transfections. Thus it appears that with further developments, it may be possible in the future to safely induce pluripotent cells from somatic cells for therapeutic applications.