論文

The seminal discovery of induced pluripotent stem cells (iPSCs) and subsequent expansion in iPSC research have greatly aided our understanding of stem cell biology and have catapulted the changing face of regenerative medicine into prominence. With easy accessibility and visibility, the skin has been considered a favorable organ to study stem cell behaviors. In particular, the skin provides valuable materials for tissue engineering and testing of novel therapeutic approaches including gene therapy and regenerative medicine. The skin consists of multiple cell lineages, including interfollicular/follicular keratinocytes, melanocytes, sebocytes, and follicular/intradermal mesenchymal cells. Nowadays, iPSCs can be generated from various skin-derived cell populations. Elegant label-tracking experiments have successfully identified their stem/early precursor cell populations. Following molecular and cellular biological experimentations and transgenic studies the elucidation of necessary factors, signaling networks, environments supporting their behavior, and interactions in organogenesis and homeostasis have been uncovered. Taking advantage of the knowledge accumulated by these works, iPSC-derived keratinocytes and melanocytes have been successfully induced, which holds promise as future materials for the bioengineering of the skin and hair, and investigation of biology of skin stem cells. Recently, the concept of cancer stem cells (CSCs) has been proposed. Cancer stem cells have been implied to originate from stem cell subsets and, accordingly, iPSCs may be converted to skin CSCs, especially most life-threatening melanoma CSCs. Those iPSC-derived CSCs may significantly enhance our understanding of cancer biology and allow the development of novel therapeutic strategies. Recently, patient-specific iPSCs were established from intractable genodermatoses, including epidermolysis bullosa, and corrected for their genetic defects. Thus, iPSC technology should open a new era of stem cell biology, genetic/regenerative medicine and oncology in the field of dermatology.

Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.