Abstract
Induced pluripotent stem cell (iPSC) technology can be used to model human disorders, create cell-based models of human diseases, including neurodegenerative diseases, and in establishing therapeutic strategies. To detect subtle cellular abnormalities associated with common late-onset disease in iPSCs, valid control iPSCs derived from healthy donors free of serious late-onset diseases are necessary. Here, we report the generation of iPSCs from fibroblasts obtained immediately postmortem from centenarian donors (106- and 109-years-old) who were extremely healthy until an advanced age. The iPSCs were generated using a conventional method involving OCT4, SOX2, KLF4, and c-MYC, and then differentiated into neuronal cells using a neurosphere method. The expression of molecules that play critical roles in late-onset neurodegenerative diseases by neurons differentiated from the centenarian-iPSCs was compared to that of neurons differentiated from iPSCs derived from familial Alzheimer's disease and familial Parkinson's disease (PARK4: triplication of the α synuclein gene) patients. The results indicated that our series of iPSCs would be useful in neurodegeneration research. The iPSCs we describe, which were derived from donors with exceptional longevity who were presumed to have no serious disease risk factors, would be useful in longevity research and as valid super-controls for use in studies of various late-onset diseases.
Highlights
In 2006, Takahashi et al directly reprogrammed somatic cells into induced pluripotent stem cells, thereby opening a novel approach to disease modeling and drug discovery [1,2]
A heat map analysis showed that the global gene expression profile of this clone, including expression of genes closely associated with longevity (insulin-like growth factor 1, IGFlike family receptor 1, sirtuin 1 and 2, and forkhead box O1), was similar to the gene expression profile of the well-established Induced pluripotent stem cell (iPSC) line 201B7 originally derived from a 36-year-old Caucasian female [1] (Figure S2)
Because biochemical and/or cellular abnormalities associated with sporadic neurodegenerative diseases may not be prominent, comparing and analyzing subtle abnormalities linked to these disease processes must await the development of valid normative control iPSCs
Summary
In 2006, Takahashi et al directly reprogrammed somatic cells into induced pluripotent stem cells (iPSCs), thereby opening a novel approach to disease modeling and drug discovery [1,2]. A major obstacle to iPSC studies of common late-onset neurodegenerative diseases remains the lack of appropriate control iPSCs. Because most studies conducted to date using patient-specific iPSCs have focused on congenital or hereditary diseases, the control iPSCs used, which are derived from so-called healthy volunteers, are not excluded from the risks associated with common late-onset diseases. To detect subtle biochemical and/or cellular abnormalities associated with common late-onset diseases using iPSCs, super-control iPSCs derived from extremely healthy donors clinically determined to be free of serious late-onset diseases are necessary. Very elderly people who are in excellent health would be expected to present few risk factors for late-onset neurodegenerative diseases, and would represent a valid control population [9]. No clinical information is available indicating whether these iPSCs would be suitable for use as a control for late-onset diseases
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