The induction of four transcription factors, KLF4, MYC, POU5F1, and SOX2, was found to allow derivation of embryonic stem cell-like pluripotent cells, now referred to as iPSCs, from mouse and later human somatic cells [6, 7]. technology, and how integration of genome editing to rare disease research will help to improve our understanding of disease pathogenesis and lead to individual therapies. modeling and analysis of human diseases was revolutionized by the discovery of reprogramming mature cells to pluripotency by Kazutoshi Takahashi and Shinya Yamanaka in 2006. The induction of four transcription factors, KLF4, MYC, POU5F1, and SOX2, was found to allow derivation of embryonic stem cell-like pluripotent cells, now referred to as iPSCs, from mouse and later Roquinimex human somatic cells [6, 7]. The simplicity of these experiments was surprising given the complexity of reprogramming experiments leading up to its discovery. The use of somatic cell nuclear transfer (SCNT) exhibited in by Sir John Gurdon in 1958 and later in mammals with the cloning of Dolly the sheep by Wilmut et al. in 1996 suggested complex mechanisms encompassing genetic and epigenetic changes controlled cellular de-differentiation [8, 9]. Therefore, the ability of a quartet of transcription factors to yield pluripotent cells largely indistinguishable from human ES cells was amazing. This seminal work also opened up new possibilities for the use of iPSCs in disease and gene-specific applications. The Yamanaka studies and subsequent publications from other labs also helped alleviate some of the ethical debates surrounding human pluripotent stem cells by avoiding stem cell isolation from your embryonic inner cell mass. Since their initial discovery, iPSCs have shown great potential in modeling the pathogenesis of rare diseases. Traditional methods have often relied upon main or patient-derived immortalized cell lines to study the etiology and physiology of rare conditions. While main cell types are readily available from blood or tissue biopsies, disease relevant cell types are not usually very easily isolated nor may they be propagated indefinitely. Moreover, immortalized cell lines are often not an accurate reflection of their main culture counterparts, limiting their reliability in functional studies. Similarly, despite being an irreplaceable tool to date for validation, animal models do Roquinimex not usually recapitulate human pathogenesis . There are considerable anatomic, embryonic, and metabolic differences between mice and humans which may reflect troubles in translating therapeutic discoveries to clinical trials . 2.1 Advantages of iPSCs for disease modeling Patient-derived iPSCs offer an invaluable alternative for modeling rare diseases, directly addressing some of the challenges associated with traditional methods (Determine 1). Along with the capacity to propagate indefinitely, iPSCs have the potential to differentiate into virtually any human cell type given the proper environmental stimuli. By utilizing this pluripotent capacity in iPSCs transporting Roquinimex specific pathogenic mutations, patient-specific iPSCs can model the molecular mechanisms underlying disease pathophysiology. The hope for iPSCs in regenerative medicine and cell therapy applications are further fueled by the potential immune compatibility of iPSC derivatives in autologous settings, suggesting a lessened risk for graft rejection compared to more common allogeneic stem cell-based therapies . Indeed, ongoing clinical studies utilizing iPSCs as a source for transplantable cellular derivatives, such as retinal pigment epithelium for treatment of age-related macular degeneration, have exhibited tissue engraftment >1 yr. post-transplantation to patients, providing hope for the continued success of regenerative therapies . Open in a separate window Physique 1 iPSC generation and potential uses of iPSC-derivatives for rare disease studies. Stem cell-based models have been successfully used to study disorders of varying genetic origin. Monogenic-based rare disorders are, thus far, the most widely analyzed using iPSC methods, particularly when a clear cellular phenotype has been established . Given the genetic basis for most rare disorders, iPSCs are particularly well adapted for this Roquinimex purpose. Additionally, rare child years diseases of developmental origin can be robustly modeled using directed differentiation assays . However, recapitulating mature cell defects of late onset disorders Akt1 has proven to be more challenging as some differentiation protocols better reflect immature rather than adult cell types [16, 17]. Several studies have utilized cell stressors, such as hydrogen peroxide or antibiotics, to generate ROS promoting mitochondrial stress to induce cellular aging.