Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging

Miller, Joseph S.; Ganat, Yosif; Kishinevsky, Sarah; Bowman, Robert L.; Liu, Becky; Tu, Edmund Y.; Mandal, Pankaj Kumar; Vera, Elsa; Shim, Jae Won; Kriks, Sonja; Taldone, Tony; Fusaki, Noemi; Tomishima, Mark; Krainc, Dimitri; Milner, Teresa A.; Rossi, Derrick J.; Studer, Lorenz

doi:10.1016/j.stem.2013.11.006

Cited by 642 publications

(691 citation statements)

References 56 publications

(67 reference statements)

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“…In this regard, it is encouraging that (1) a model of human midbrain organoids produced neuromelanin, a dark pigment found in adult midbrains, after 2 months of culture;33 (2) long‐term cultured AD iPSC‐based brain organoids recapitulated both A β and tau pathology in a sequential manner 44. Further development in incorporation of other relevant cell types60 and accelerating maturation and/or aging in a dish67 would be extremely exciting and important.…”

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

“…The existence of genetic forms of premature aging diseases (including Hutchinson–Gilford progeria syndrome and Werner syndrome), provides us with another means of accelerating aging in a dish. Studies have shown that introduction of these disease‐causing genetic variants into otherwise wild‐type cells recapitulates many aspects of cellular aging 67. Taking this approach into 3D brain organoids may be potentially very useful for inducing adult or aged phenotypes within an experimentally feasible time frame.…”

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

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Translational potential of human brain organoids

Sun

Tan

2018

Ann Clin Transl Neurol

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The recent technology of 3D cultures of cellular aggregates derived from human stem cells have led to the emergence of tissue‐like structures of various organs including the brain. Brain organoids bear molecular and structural resemblance with developing human brains, and have been demonstrated to recapitulate several physiological and pathological functions of the brain. Here we provide an overview of the development of brain organoids for the clinical community, focusing on the current status of the field with an critical evaluation of its translational value.

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Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

Section: Current Limitations Of Brain Organoidsmentioning

confidence: 99%

Translational potential of human brain organoids

Sun

Tan

2018

Ann Clin Transl Neurol

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“…For example, this issue of accelerated maturation has been partially resolved by mimicking aging in iPSCs by overexpressing progerin [36]. This process introduces an added variable and is not applicable to all cell types.…”

Section: Modeling Disease Using Human Cells In General and Psc-derivementioning

confidence: 99%

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

Hunsberger

Efthymiou

Malik

et al. 2015

Stem Cells and Development

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There is great need to develop more predictive drug discovery tools to identify new therapies to treat diseases of the central nervous system (CNS). Current nonpluripotent stem cell-based models often utilize non-CNS immortalized cell lines and do not enable the development of personalized models of disease. In this review, we discuss why in vitro models are necessary for translational research and outline the unique advantages of induced pluripotent stem cell (iPSC)-based models over those of current systems. We suggest that iPSC-based models can be patient specific and isogenic lines can be differentiated into many neural cell types for detailed comparisons. iPSC-derived cells can be combined to form small organoids, or large panels of lines can be developed that enable new forms of analysis. iPSC and embryonic stem cell-derived cells can be readily engineered to develop reporters for lineage studies or mechanism of action experiments further extending the utility of iPSC-based systems. We conclude by describing novel technologies that include strategies for the development of diversity panels, novel genomic engineering tools, new three-dimensional organoid systems, and modified high-content screens that may bring toxicology into the 21st century. The strategic integration of these technologies with the advantages of iPSC-derived cell technology, we believe, will be a paradigm shift for toxicology and drug discovery efforts.Disease Modeling D iseases of the central nervous system (CNS) affect a large number of people, but therapeutic intervention is hampered by the lack of useful models for many of these diseases. Current research on human subjects, particularly for drug discovery for CNS diseases, is severely (and appropriately) limited by ethical guidelines. Therefore, surrogate models are needed that share important anatomical, physiological, and genetic features to advance new treatments and therapies for CNS diseases [1].Developing rapid and effective therapies for CNS diseases requires the availability of in vitro models that accurately recapitulate disease phenotypes and predict patient treatment response. A proper model must be both sensitive and predictive while reflecting both normal and disease processes. Equally important, these models should enable the investigation of genetic and environmental risk factors contributing to diseases in a rapid and economical way. Currently used models often do not reflect a typical human response [2-4], despite efforts underway to better characterize these models and increase their preclinical value in predicting safety and efficacy in the clinic [5,6]. Therefore, there is a great need to develop disease-and patient-specific models from cells directly affected in CNS disorders. These cellbased models, we envision, could either replace or supplement current animal models and enable the efficient translation of basic research into the clinical setting. Limitations with current CNS modelsCurrently, drug discovery relies on the use of animalbased or cell-based models, ...

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“…We have recently proposed that aging should be incorporated as an independent factor for the in vitro modeling of late-onset diseases. In a first such attempt, we hijacked the molecular mechanisms responsible for Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder, to model late-onset degenerative features of Parkinson's disease (PD) in an iPSC-derived lineage (Miller et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease

Vera

Studer

2015

Development

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In contrast to the successful modeling of early-onset disorders using patient-specific cells, modeling of late-onset neurodegenerative diseases such as Parkinson's disease remains a challenge. This might be related to the often ignored fact that current induced pluripotent stem cell (iPSC) differentiation protocols yield cells that typically show the behavior of fetal stage cells. Acknowledging aging as a contributing factor in late-onset neurodegenerative disorders represents an important step on the road towards faithfully recreating these diseases in vitro. Here, we summarize progress in the field and review the strategies and challenges for triggering late-onset disease phenotypes.

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Human iPSC-Based Modeling of Late-Onset Disease via Progerin-Induced Aging

Cited by 642 publications

References 56 publications

Translational potential of human brain organoids

Translational potential of human brain organoids

Induced Pluripotent Stem Cell Models to Enable In Vitro Models for Screening in the Central Nervous System

When rejuvenation is a problem: challenges of modeling late-onset neurodegenerative disease

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