Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery

Abstract

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

The progress of Stem cells in the treatment of diabetes mellitus type 1

“…IPSCs like ESCs have infinite self-renewal capacity and great potential to differentiate into a wide variety of cell types (Yu et al, 2007). Undifferentiated iPSCs can be maintained as cell lines; this provides great promise for disease modeling and allowing the generation of personalized stem cells for autologous cell therapies (Jang et al, 2012). Mouse skin fibroblast-derived iPSCs were able to differentiate into β-like cells, similar to normal, endogenous insulinsecreting cells that managed to control hyperglycemia in diabetic mice (Alipio et al, 2010).…”

Diabetes mellitus and cellular replacement therapy: Expected clinical potential and perspectives

“…Contemporary biological and analytical techniques help us to predict the transcription factors that are needed for β-cell regeneration and restoring of the β-cell mass [62] . The transcription factors mediate β-cell renewing with diverse culturing methods [63] .…”

The Pharmacology of Regenerative Medicine

“…Examples of specific conditions for which patient-specific iPS cells have been obtained and differentiated into disease-relevant cell types include Parkinson's disease (Byers et al, 2012;Jang et al, 2012) and other neurodegenerative disorders Jung et al, 2012), Wilson's disease (Yi et al, 2012), lysosomal storage disorders (Huang et al, 2012b), and diabetes (Fujikura et al, 2012).…”