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  • Review Article
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Induced pluripotent stem cells: the new patient?

Nature Reviews Molecular Cell Biology volume 13, pages 713–726 (2012)Cite this article

Subjects

Key Points

  • Human induced pluripotent stem (iPS) cells resemble human embryonic stem (ES) cells and have the potential to differentiate into all somatic cell types of the body. Cardiomyocytes and neurons can be derived by using various protocols, but their phenotype is immature, and different subtypes are difficult to obtain and purify.

  • Human iPS cells provide opportunities to capture the heterogeneity that arises from gender, ethnicity and gene modifiers specific to patients from which they have been derived. Although human ES cells have higher genetic stability than human iPS cells, both cell types can be genetically manipulated to generate genotyped matched cell lines, allowing direct comparison of disease-specific genotypes.

  • Both integrating and non-integrating methods are available for reprogramming. Non-integrating approaches are generally preferred but may be less efficient or more labour intensive.

  • iPS cell technology is particularly suitable for modelling diseases and is of special interest for cardiology and neurosciences in which the isolation of primary human tissue is invasive and potentially harmful. Several proof-of-concept studies have recapitulated both genetic and complex diseases of the heart, for example long QT syndrome and catecholaminergic ventricular tachycardia, and the brain, for example, Parkinson's disease, Rett syndrome and schizophrenia.

  • Patient-specific human iPS cell lines are useful for studying drug–gene interactions and for the evaluation of the potency of candidate drugs in reversing aberrant phenotypes that are associated with disease and ameliorating pathological traits. Examples include β-blockade treatment and ion channel activators and inhibitors for cardiac arrhythmogenic disorders, and anti-psychotic drugs or insulin-growth factor application for schizophrenia and autism spectrum disorders, respectively.

  • Availability of larger cohorts of patients, possibly representing different ethnic backgrounds, will help in generalizing effectiveness of therapies and drug adverse effects.

Abstract

Worldwide increases in life expectancy have been paralleled by a greater prevalence of chronic and age-associated disorders, particularly of the cardiovascular, neural and metabolic systems. This has not been met by commensurate development of new drugs and therapies, which is in part owing to the difficulty in modelling human diseases in laboratory assays or experimental animals. Patient-specific induced pluripotent stem (iPS) cells are an emerging paradigm that may address this. Reprogrammed somatic cells from patients are already applied in disease modelling, drug testing and drug discovery, thus enabling researchers to undertake studies for treating diseases 'in a dish', which was previously inconceivable.

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Figure 1: Human iPS cell derivation, differentiation and applications.
Figure 2: Human iPS cells in modelling cardiac and neural diseases.

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Acknowledgements

The authors thank L. Studer for sharing insights on the familial dysautonomia human induced pluripotent stem cell model and R.P. Davis for constructive comments on the manuscript. Work in the Mummery laboratory was supported by a grant from the Dutch government to the Netherlands Institute for Regenerative Medicine (NIRM, grant No. FES0908) and M.B. is supported by the EU Marie Curie FP7-people-2011-IEF programme (HPSCLQT No. 29999).

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Authors and Affiliations

  1. Department of Anatomy and Embryology, Leiden University Medical Center, Einthovenweg 20, ZC Leiden, 2333, The Netherlands

    Milena Bellin & Christine L. Mummery

  2. Salk Institute, 10010 North Torrey Pines Road, La Jolla, 92037, California, USA

    Maria C. Marchetto & Fred H. Gage

Authors
  1. Milena Bellin
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  2. Maria C. Marchetto
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  3. Fred H. Gage
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  4. Christine L. Mummery
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Correspondence to Fred H. Gage or Christine L. Mummery.

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FURTHER INFORMATION

Christine L. Mummery's homepage

Coriell Institute Biobank Catalog

UK Stem Cell Bank

California Institute for Regenerative Medicine (CIRM)

Innovative Medicine Initiative (IMI)

Center for iPS Cell Research and Application (CiRA) Kyoto University

Core Facility Activities, Rutgers The State University of New Jersey

Glossary

Somatic cell nuclear transfer

Reprogramming technique in which a nucleus from a differentiated somatic cell is transplanted into an enucleated oocyte.

Cell co-culture system

In vitro differentiation technique in which pluripotent stem cells are cultured together with another cell type that is able to induce and support the specification of a particular lineage by mimicking in vivo tissue niches.

Neurite

A projection from the cell body of a neuron.

Homologous recombination

A type of genetic recombination in which DNA is exchanged between two DNA molecules that share high sequence similarity. This process is exploited for genetic manipulation of mouse and human embryonic stem cells.

Glial cells

Non-neuronal cells that provide support and protection for neurons in the brain and in other parts of the nervous system.

Sarcomere

The contractile unit of the skeletal and cardiac muscle fibre that consists of several contractile proteins.

Cortical neurons

Nerve cells that make up the cerebral cortex, which is the outer part of the brain.

Synapses

Structures that, in the nervous system, allow a neuron to communicate with another cell. The transmitted signal can be electrical or chemical (neurotransmitter).

Zinc-finger nucleases

(ZNFs). Artificial proteins that contain a sequence-specific DNA-binding domain (composed of engineered zinc-finger arrays) fused to a nuclease domain (from the FokI restriction enzyme). ZNFs cleave DNA in a non-sequence-specific manner.

Transcription activator-like effector nucleases

(TALENs). Like ZFNs, they consist of a non-specific FokI nuclease domain fused to a DNA-binding domain derived from bacterial transcription activator-like effectors (TALEs).

Adult progenitor cells

Self-renewing precursor cells that are present in some adult tissues and that are able to produce one or more specialized cell types.

Long QT syndromes

(LQTSs). Channelopathies characterized by a prolongation of the QT interval in the electrocardiogram and a propensity to ventricular tachycardia and sudden death. These syndromes are not associated with concomitant structural cardiac abnormalities.

Brugada syndromes

Channelopathies characterized by a specific electrocardiographic pattern and susceptibility to ventricular arrhythmia and sudden death. These syndromes are not associated with concomitant structural cardiac abnormalities.

Action potential duration

(APD). Duration of the event in which the membrane potential of an electrically excitable cell rises and falls.

Inward Na+ current

The specific Na+ current that passes through the Na+ channel SCN5A. This current is present at the surface of cardiac cells and is essential for the beginning of an action potential.

Familial dysautonomia

A rare but fatal peripheral neuropathy that is characterized by the degeneration and depletion of autonomic and sensory neurons.

Rett syndrome

(RTT). A progressive neurological disorder in which patients show a large spectrum of autistic characteristics.

Penetrance

In genetics, the proportion of individuals within a population carrying a mutation that causes a particular trait and that exhibits the specific associated clinical symptoms.

Roscovitine

A compound that selectively inhibits cyclin-dependent kinases and increases the (voltage-dependent) inactivation of the l-type Ca2+ channel CACNA1C.

Calpain

A family of Ca2+-dependent proteases that has an important role in the signal transduction pathway by catalysing the controlled proteolysis of target proteins.

Ataxin 3

(ATXN3). A deubiquitylating enzyme that is involved in protein homeostasis maintenance, transcription, cytoskeleton regulation, myogenesis and degradation of misfolded chaperone substrates.

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Bellin, M., Marchetto, M., Gage, F. et al. Induced pluripotent stem cells: the new patient?. Nat Rev Mol Cell Biol 13, 713–726 (2012). https://doi.org/10.1038/nrm3448

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