Key Points
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This Review describes recent progress in directing human pluripotent stem cells (hPSCs) into specific progeny that could have therapeutic purposes for a range of diseases. It also addresses major hurdles in the transition of hPSC-based cell therapies from the bench to the bedside.
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Neural induction of hPSCs can be achieved in several ways. Recent protocols use defined neural inducers — such as inhibitors of transforming growth factor-β (TGFβ) and bone morphogenetic protein (BMP) (that is, dual SMAD inhibition) — to greatly enhance the efficiency and the speed of neural induction.
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The derivation of dopamine neurons from hPSCs has been achieved a decade ago, but the cells did not show good engraftment. Recent data shows that those neurons lacked expression of forkhead box protein A2 (FOXA2), which is a DNA-binding transcription factor that is fundamental for authentic midbrain identity.
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A novel protocol derives dopamine neurons through a floor plate intermediate, which show genetic, biochemical and physiological features of authentic midbrain neurons. They also survive and ameliorate Parkinson's disease-like behaviour in vivo.
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Improved protocols for the derivation of medium spiny striatal neurons from hPSCs has been reported, and evidence shows survival and behavioural improvement in a lesion model of Huntington's disease.
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The derivation of glial cells from hPSCs is faced with the challenge of protracted developmental timing in vitro, which is similar to the in vivo situation. The derivation of oligodendrocytes has been achieved using long-term in vitro cultures; these cells have been grafted in neonatal Shiverer-expressing mice with good cell survival, remyelination and extended lifespan in these mice.
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The current derivation of non-neural cell types — such as cardiomyocytes, pancreatic islet cells and engraftable haematopoietic stem cells — faces substantial challenges owing to the immature nature of the differentiated cells (for cardiomyocytes), the need for in vivo differentiation (for pancreatic islet cells) and poor in vivo homing (for haematopoietic stem cells).
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New developments in cell differentiation include the use of potent small molecules that allow the direct manipulation of multiple signalling pathways and, in some cases, the acceleration of differentiation timelines. Other approaches include cell purification and three-dimensional cultures that harness the self-organizing potential of hPSC-derived lineages.
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Defining cell identity in vitro is a fundamental element in designing directed differentiation strategies and includes expression of cell type-specific markers, transcriptional profiles and assessments of the epigenetic or enhancer landscapes. Assessment of in vivo function includes electrophysiology, the use of genetically encoded calcium sensors, microdialysis and optogenetic techniques, as well as behavioural studies.
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Autologous cell sources, such as patient-derived induced pluripotent stem cells, are of great interest but currently face substantial hurdles for clinical implementation that are related to safety and regulatory requirements. The translation of direct reprogramming and nuclear transfer strategies are in early stages of development.
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A spinal cord trial using human embryonic stem cell (hESC)-derived oligodendrocytes has not reported any major adverse effects, although the trial has been abandoned. Ongoing clinical trials using hESC-derived retinal pigment epithelial in eye repair are promising.
Abstract
After years of incremental progress, several recent studies have succeeded in deriving disease-relevant cell types from human pluripotent stem cell (hPSC) sources. The prospect of an unlimited cell source, combined with promising preclinical data, indicates that hPSC technology may be on the verge of clinical translation. In this Review, we discuss recent progress in directed differentiation, some of the new technologies that have facilitated the success of hPSC therapies and the remaining hurdles on the road towards developing hPSC-based cell therapies.
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Acknowledgements
The authors' own work described in this Review was supported by New York State Stem Cell Board (NYSTEM) (C028503) and the US National Institute of Neurological Disorders (5R01NS054009 to V.T.; NS052671 and NS084334 to L.S.).
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Glossary
- Directed differentiation
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A method to control the differentiation of pluripotent stem cells into specific cell types, which is typically achieved by providing cells with extrinsic signals in a precise temporal sequence that mimicks development.
- Morphogen
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A substance that is active in pattern formation and that varies in spatial concentration or activity; cells respond differently at different threshold concentrations of morphogens.
- Embryoid body
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A clump of cells that arises when embryonic cells are cultured and differentiated in suspension and that can give rise to cell types from all three germ layers (that is, the endoderm, mesoderm and ectoderm).
- Stromal
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Pertaining to connective tissue that is made up of both cells (such as fibroblasts) and matrix (such as collagen).
- Dopamine neuron
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A nerve cell that uses the neurotransmitter dopamine; those in the midbrain are affected in Parkinson's disease.
- Dual SMAD inhibition
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(dSMADi). The concomitant inhibition of bone morphogenetic protein and Nodal–activin–transforming growth factor-β signalling, which is used to obtain neural cells from human pluripotent stem cell sources.
- Floor plate
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A transient developmental structure along the midline of the embryo that is important for brain development.
- Striatal neurons
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Neurons that lie in the striatum, which is an area of the brain that is involved in fine movements, emotion and cognition.
- Globus pallidus
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A subcortical structure of the brain that is a major element of the basal ganglia system.
- Oligodendrocytes
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One of the three main cell types that make up the brain parenchyma, the other two being neurons and astrocytes. They produce myelin, which insulates axons to alter the conduction properties of neurons.
- Self-organizing
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Pertaining to an intrinsic programme in pluripotent stem cell-derived lineages that enables cells in vitro to assemble into tissue-like and organoid structures.
- Transcription activator-like effector nucleases
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(TALENs). Fusions of truncated TALEs to a nonspecific DNA-cleavage domain of the FokI endonuclease. Each TALE contains an amino terminus, a custom-designed DNA-binding domain and a carboxyl terminus with the activation domain being removed.
- Positron emission tomography
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(PET). An imaging technique that detects the emission of positrons from the brain after a small amount of radioactive isotopes have been injected into the blood stream; it is used to quantitatively measure metabolic, biochemical and functional activity in living tissues.
- Good manufacturing practice
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(GMP). A set of standardized production and testing conditions that are required for developing a clinical-grade cell product and for obtaining regulatory approval for trials in human subjects.
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Tabar, V., Studer, L. Pluripotent stem cells in regenerative medicine: challenges and recent progress. Nat Rev Genet 15, 82–92 (2014). https://doi.org/10.1038/nrg3563
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DOI: https://doi.org/10.1038/nrg3563
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