Specification of motoneurons from human embryonic stem cells

Li, Xue Jun; Du, Zhong Wei; Żarnowska, Ewa D.; Pankratz, Matthew; Hansen, Lauren; Pearce, Robert A.; Zhang, Su Chun

doi:10.1038/nbt1063

Cited by 728 publications

(789 citation statements)

References 30 publications

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“…3A). The transduced cells were subjected to differentiation using a well-established protocol [24]. Like H9 cells, both SMA-23/Neo and SMA-23/ SMN cells formed neuron-like cells in culture.…”

Section: Resultsmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders in humans and is a common genetic cause of infant mortality. The disease is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord and muscular atrophy in the limbs and trunk. One function of SMN involves RNA splicing. It is unclear why a deficiency in a housekeeping function such as RNA splicing causes profound effects only on motoneurons but not on other cell types. One difficulty in studying SMA is the scarcity of patient's samples. The discovery that somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) raises the intriguing possibility of modeling human diseases in vitro. We reported the establishment of five iPSC lines from the fibroblasts of a type 1 SMA patient. Neuronal cultures derived from these SMA iPSC lines exhibited a reduced capacity to form motoneurons and an abnormality in neurite outgrowth. Ectopic SMN expression in these iPSC lines restored normal motoneuron differentiation and rescued the phenotype of delayed neurite outgrowth. These results suggest that the observed abnormalities are indeed caused by SMN deficiency and not by iPSC clonal variability. Further characterization of the cellular and functional deficits in motoneurons derived from these iPSCs may accelerate the exploration of the underlying mechanisms of SMA pathogenesis.

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Section: Resultsmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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“…Bioresponsiveness could be particularly relevant in studying and manipulating 'emergent' processes, such as stem cell differentiation, in which hydrogel properties that are appropriate in the early stages are likely to be dramatically different from those needed later on. For example, recent studies in standard cell culture indicate that human embryonic stem cell differentiation into spinal motor neurons 85 or cardiomyocytes 86 can be amplified by mimicking the timed soluble signalling regimen observed during early tissue development, and that the timing of signal delivery is critical. One can envision a more intelligent embodiment of this approach, in which a hydrogel responds to a change in stem cell phenotype (for example, initial lineage commitment) by changing local physical properties or by delivering a specific growth factor, thereby optimizing new tissue formation.…”

Section: Triggered Changes In Hydrogel Propertiesmentioning

confidence: 99%

Moving from static to dynamic complexity in hydrogel design

2012

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Hydrogels are water-swollen polymer networks that have found a range of applications from biological scaffolds to contact lenses. Historically, their design has consisted primarily of static systems and those that exhibit simple degradation. However, advances in polymer synthesis and processing have led to a new generation of dynamic systems that are capable of responding to artificial triggers and biological signals with spatial precision. These systems will open up new possibilities for the use of hydrogels as model biological structures and in tissue regeneration.H ydrogels are water-swollen polymer networks that have been used for many decades, with applications as varied as contact lenses and super-absorbant materials. As the field of biomedical engineering has developed, hydrogels have become a prime candidate for application as molecule delivery vehicles and as carriers for cells in tissue engineering, owing to their ability to mimic many aspects of the native cellular environment (for example, high water content, mechanical properties that match soft tissues). Traditional hydrogels, formed through the covalent and non-covalent crosslinking of polymer chains, were regarded as relatively inert materials, providing a simple biomimetic three-dimensional (3D) environment, either for tissue production by local resident cells or for positioning of cells delivered in vivo. However, the simplicity of these materials may have in fact hindered their application, restricting cellular interactions with the environment and preventing uniform extracellular matrix (ECM) production and proper tissue development. In addition, these materials were limited to modelling static environments and lacked the spatiotemporal dynamic properties relevant for complex tissue processes. Fortunately, during the last decade the concepts of hydrogel design and cellular interaction have evolved, shedding light on how they may control cell behaviour, particularly for tissue engineering applications.Hydrogels with a range of mechanical properties, and capable of incorporating a wide range of biologically relevant molecules, from individual functional groups to multidomain proteins, are currently in development 1 . In addition, hydrogels are being designed with spatial heterogeneity, to either replicate properties in native tissue structures or to produce constructs with distinct regionally specific cell behavior 2 . As a result, studies to date have clearly demonstrated the possibility of creating well-defined microenvironments with control over the 3D presentation of signals to cells 3 . However, recently there has been a focus on the concept of hydrogels that exhibit dynamic complexity. These materials should evolve with time and in response to

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“…Next, in order to differentiate the ventral spinal cells, specifically motor neurons (MN) (Li et al, 2005;Hu and Zhang, 2009) and oligodendrocytes (OL) (Hu et al, 2009a), the early neuroepithelia were treated with 0.1 μmol/L of RA during day 10-17 of differentiation. This will have these naïve neural stem cells adopt spinal cell fate and subsequently differentiate into more specific subtypes of neurons or glia.…”

Section: Twist Between Spinal Motor Neuron and Oligodendrocytesmentioning

confidence: 99%

Specification of functional neurons and glia from human pluripotent stem cells

Jiang

Zhang

2012

Protein Cell

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Human pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) hold great promise in regenerative medicine as they are an important source of functional cells for potential cell replacement. These human PSCs, similar to their counterparts of mouse, have the full potential to give rise to any type of cells in the body. However, for the promise to be fulfilled, it is necessary to convert these PSCs into functional specialized cells. Using the developmental principles of neural lineage specification, human ESCs and iPSCs have been effectively differentiated to regional and functional specific neurons and glia, such as striatal gama-aminobutyric acid (GABA)-ergic neurons, spinal motor neurons and myelin sheath forming oligodendrocytes. The human PSCs, in general differentiate after the similar developmental program as that of the mouse: they use the same set of cell signaling to tune the cell fate and they share a conserved transcriptional program that directs the cell fate transition. However, the human PSCs, unlike their counterparts of mouse, tend to respond divergently to the same set of extracellular signals at certain stages of differentiation, which will be a critical consideration to translate the animal model based studies to clinical application.

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Specification of motoneurons from human embryonic stem cells

Cited by 728 publications

References 30 publications

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Moving from static to dynamic complexity in hydrogel design

Specification of functional neurons and glia from human pluripotent stem cells

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