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Pluripotent Stem Cells in Regenerative Medicine: Challenges and Recent Progress

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Pluripotent Stem Cells in Regenerative Medicine: Challenges and Recent Progress REVIEWS Pluripotent stem cells in regenerative medicine: challenges and recent progress Viviane Tabar1 and Lorenz Studer1,2 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. Directed differentiation Access to unlimited numbers of specific cell types on progress has been made in the area of neuronal lineage A method to control the demand has been a long-standing goal in regenerative specification, which is highly dependent on mimicking differentiation of pluripotent medicine. With the availability of human pluripotent in vitro the early patterning signals that impart axial stem cells into specific cell stem cells (hPSCs) and greatly improved protocols for coordinates during neural development. Both small- types, which is typically their directed differentiation, this prospect could become molecule-based and morphogen-based approaches have achieved by providing cells with extrinsic signals in a a reality for several disease-relevant cell types. Recent been developed to derive specific neuronal subtypes precise temporal sequence advances in the stem cell field indicate that the ‘holy from pluripotent stem cells. However, the replacement that mimicks development. grail’ of directed differentiation (that is, the generation of of nerve cells in traumatic or degenerative disorders of unlimited numbers of authentic and genetically matched the central nervous system (CNS) remains a daunting Morphogen A substance that is active in cell types for cell therapy) could indeed translate into task. Recent strategies for in vivo cell-fate conversion are 1–4 pattern formation and that effective therapies for currently intractable disorders , still at early stages of development but could potentially varies in spatial concentration although new challenges are likely to emerge on the road advance as an alternative approach that bypasses the or activity; cells respond towards such translation in humans. need for cell transplantation (reviewed in REF. 8). differently at different In parallel to the improvement in directed differentia- Over the years, the field of directed differentiation threshold concentrations of morphogens. tion, novel technologies have been developed to assess has used three main strategies to specify neural lineages lineage, fate and function of stem cell-derived cell types from hPSCs. These strategies are embryoid body forma- both in vitro and in vivo. Here, we review some of the tion, co‑culture on neural-inducing feeders and direct recent breakthroughs in directed differentiation and neural induction. Early protocols for embryoid body discuss their implications for cell therapy. The ability formation were based on triggering differentiation of to access patient-specific cells at scale and on demand human embryonic stem cells (hESCs) followed by selec- 6 1Center for Stem Cell Biology are also crucial for human disease modelling and hPSC- tion in serum-free media to enrich for neural lineages . and Department of based drug discovery; these applications are not dis- The development of serum-free embryoid body cultures Neurosurgery, Memorial cussed here but have been the subject of a recent review5. enabled the direct induction of neural lineages from Sloan-Kettering Cancer In this Review, we present recent breakthroughs in hPSCs, and the efficiency of serum-free embryoid body Center, 1275 York Avenue, New York 10065, USA. deriving therapeutically relevant cell types from hPSC formation could be greatly improved in the presence 2Developmental Biology sources, discuss some of the tools that made such of the Rho-associated protein kinase (ROCK) inhibi- Program, Memorial progress possible and highlight crucial next steps and tor compound Y-27632 (REF. 9) that prevents cell death Sloan-Kettering Cancer challenges on the road towards clinical translation. of dissociated hPSCs. Stromal feeder-based cultures Center, 1275 York Avenue, have also been widely used for generating neuroepi- New York 10065, USA. e-mails: [email protected]; Deriving neural cell types thelial cells and specific neural populations, includ- 10 [email protected] Neural cell types were among the first lineages to be ing midbrain dopamine neuron-like cells from hPSCs . doi:10.1038/nrg3563 reliably obtained from hPSC sources6,7. Arguably, most Although the mechanism of neural induction (that is, 82 | FEBRUARY 2014 | VOLUME 15 www.nature.com/reviews/genetics © 2014 Macmillan Publishers Limited. All rights reserved REVIEWS stromal-derived inducing activity) remains unclear and For nearly a decade, studies had shown the derivation the use of feeders would greatly complicate translational of cells with midbrain dopamine neuron-like proper- use, this approach has remained in use because of the ties10,16,17. However, those neurons lacked a subset of fea- robust induction efficiencies and the ability to combine tures, such as expression of the DNA-binding forkhead it with other neural inducing strategies. box protein A2 (FOXA2), and did not engraft efficiently. Direct induction protocols do not require embryoid We recently established a novel protocol for deriving body formation or co‑culture for neural induction. Early neurons from hESCs that is based on a more precise attempts at direct conversion were based on the simple developmental patterning of the cells (FIG. 1a). A key fea- switch of hESC cultures to serum-free culture condi- ture of this protocol is the transition of the cells through tions followed by mechanical isolation of spontaneously a floor plate intermediate stage instead of the neuroepi- appearing neural rosette cultures7. However, the use of thelial intermediate that is used in past attempts. The defined neural inducers, such as inhibitors of trans- floor plate is a transient developmental structure that forming growth factor (TGF) and bone morphogenetic has only been recently implicated in midbrain dopamine Embryoid body dual SMAD inhibition A clump of cells that arises protein (BMP) signalling (that is, neuron development. The resulting floor plate-derived when embryonic cells are (dSMADi)), have greatly enhanced the efficiency and dopamine neurons have genetic, biochemical and phy­ cultured and differentiated in the speed of neural induction11. A particularly attrac- siological features of authentic midbrain dopamine neu- suspension and that can give tive feature of dSMADi is the synchronized differen- rons, and they have been successfully tested in mouse, rise to cell types from all 1 three germ layers (that is, tiation process that yields a nearly uniform population rat and rhesus monkey models of Parkinson’s disease . A the endoderm, mesoderm of early neural cells within ten days of differentiation. key step was the activation of canonical WNT signalling and ectoderm). The use of precise patterning strategies in combination using a small-molecule inhibitor of glycogen synthase with dSMADi results in protocols for the derivation of kinase (GSK), which is a strategy that has been replicated Stromal many CNS and peripheral nervous system (PNS) line- in several additional studies since then18,19. These data Pertaining to connective tissue that is made up of both cells ages from hPSCs. However, regardless of the specific emphasize the importance of fully defining the identity (such as fibroblasts) and matrix neural induction strategy used, the main challenge over of hESC-derived neurons before implantation. (such as collagen). the past ten years has been to develop protocols that implement in vitro the early patterning events that are Striatal neurons. Huntington’s disease is a currently Dopamine neuron A nerve cell that uses the responsible for creating specific neuronal and glial cell untreatable autosomal dominant neurodegenerative neurotransmitter dopamine; types. Only recently have these strategies been refined disease and is characterized by abnormal movements, those in the midbrain are to a level that is sufficient to contemplate translational cognitive decline and various psychiatric problems. affected in Parkinson’s disease. applications for a subset of neural lineages. Recent pro- The genetic cause of the disease is an expansion of gress for three relevant hPSC-derived neural lineages is CAG repeats within the huntingtin gene (HTT)20. Dual SMAD inhibition (FIG. 1) striatal neurons (dSMADi). The concomitant discussed below . Medium spiny are the most severely inhibition of bone affected cell type in patients with Huntington’s disease. morphogenetic protein and Dopamine neurons. Parkinson’s disease is the second There is a long history of fetal tissue-grafting studies Nodal–activin–transforming most common neurodegenerative disorder and is in Huntington’s disease21 that aimed to replace striatal growth factor-β signalling, which is used to obtain neural charac­terized by the progressive loss of several neural neurons. Similarly to Parkinson’s disease, decades of cells from human pluripotent cell types in the CNS and PNS. Although the causes of experience from the fetal tissue-grafting studies could stem cell sources. Parkinson’s
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