Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

Ma, Lixiang; Hu, Baoyang; Liu, Yan; Vermilyea, Scott C.; Liu, Huisheng; Gao, Lu; Sun, Yan; Zhang, Xiaoqing; Zhang, Su Chun

doi:10.1016/j.stem.2012.01.021

Cited by 264 publications

(314 citation statements)

References 59 publications

(69 reference statements)

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“…6). YAP activity is decreased during mammalian neurogenesis (19,36,37) in conjunction with Sonic Hedgehog (36,37) and Smad (38) signaling pathways, which are ubiquitous targets of soluble factors used to promote neuronal differentiation of hES cells (39)(40)(41)(42)(43)(44)(45)(46).…”

Section: Resultsmentioning

confidence: 99%

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Musah¹,

Wrighton

Zaltsman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

159

174

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Physical stimuli can act in either a synergistic or antagonistic manner to regulate cell fate decisions, but it is less clear whether insoluble signals alone can direct human pluripotent stem (hPS) cell differentiation into specialized cell types. We previously reported that stiff materials promote nuclear localization of the Yes-associated protein (YAP) transcriptional coactivator and support long-term self-renewal of hPS cells. Here, we show that even in the presence of soluble pluripotency factors, compliant substrata inhibit the nuclear localization of YAP and promote highly efficient differentiation of hPS cells into postmitotic neurons. In the absence of neurogenic factors, the effective substrata produce neurons rapidly (2 wk) and more efficiently (>75%) than conventional differentiation methods. The neurons derived from substrate induction express mature markers and possess action potentials. The hPS differentiation observed on compliant surfaces could be recapitulated on stiff surfaces by adding small-molecule inhibitors of F-actin polymerization or by depleting YAP. These studies reveal that the matrix alone can mediate differentiation of hPS cells into a mature cell type, independent of soluble inductive factors. That mechanical cues can override soluble signals suggests that their contributions to early tissue development and lineage commitment are profound.H uman pluripotent stem (hPS) cells, which include human embryonic (hES) and human induced pluripotent stem cells, possess the remarkable capacity to self-renew indefinitely and differentiate into almost any specialized cell type (1, 2). They represent a potentially unlimited supply of cells for regenerative medicine, drug screening, and studies of human development. These applications require efficient and reproducible conditions to direct hPS cell differentiation into specialized cell types, including neuronal cells. To date, the focus has been on identifying soluble factors, such as growth factors and small molecules, that can influence hPS cell differentiation. The ability of insoluble signals to promote hPS cell-lineage specification remains less clear.Studies in murine ES cells (3, 4) and tissue-specific stem cells (5-10) indicate that the adhesive and mechanical properties of the substratum used can influence cell fate decisions (11). For example, human mesenchymal stem (hMS) cells are sensitive to changes in substrate elasticity and respond by differentiating toward distinct cell lineages depending on the stiffness of the matrix (5). These hMS cells, however, tend to exist in heterogeneous cell populations and lack a specific and unique cell characterization marker (12). Their differentiation capacity is restricted to a few tissues that arise from the mesoderm lineage, such as bone, fat, and cartilage. Indeed, there are questions about whether these cells undergo transdifferentiation to cell types, such as neurons (12)(13)(14). With the unique ability to differentiate into almost any cell type, hPS cells serve as an excellent model for und...

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Section: Resultsmentioning

confidence: 99%

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Musah¹,

Wrighton

Zaltsman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

159

174

View full text Add to dashboard Cite

show abstract

“…From skin biopsies of ChAc patients and age-matched healthy control subjects, we established a novel iPSC-based human model system to study the neuropathology of the disease. In this study, we used a differentiation protocol based on neural induction, regional patterning toward a lateral ganglionic eminence identity, and terminal differentiation to striatal MSNs (Aubry et al, 2008;Ma et al, 2012;Delli Carri et al, 2013;Golas and Sander, 2016), the cell type that is mainly affected by the neurodegenerative process, as shown by histopathological analysis and magnetic resonance imaging of ChAc patients (Hardie et al, 1991;Kutcher et al, 1999;Walterfang et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Stanslowsky¹,

Reinhardt

Glaß³

et al. 2016

J. Neurosci.

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Chorea-acanthocytosis (ChAc) is a fatal neurological disorder characterized by red blood cell acanthocytes and striatal neurodegeneration.Recently, severe cell membrane disturbances based on depolymerized cortical actin and an elevated Lyn kinase activity in erythrocytes from ChAc patients were identified. How this contributes to the mechanism of neurodegeneration is still unknown. To gain insight into the pathophysiology,weestablishedaChAcpatient-derivedinducedpluripotentstemcellmodelandanefficientdifferentiationprotocolprovidingalarge population of human striatal medium spiny neurons (MSNs), the main target of neurodegeneration in ChAc. Patient-derived MSNs displayed enhanced neurite outgrowth and ramification, whereas synaptic density was similar to controls. Electrophysiological analysis revealed a pathologically elevated synaptic activity in ChAc MSNs. Treatment with the F-actin stabilizer phallacidin or the Src kinase inhibitor PP2 resulted in the significant reduction of disinhibited synaptic currents to healthy control levels, suggesting a Src kinase-and actin-dependent mechanism. This was underlined by increased G/F-actin ratios and elevated Lyn kinase activity in patient-derived MSNs. These data indicate that F-actin stabilization and Src kinase inhibition represent potential therapeutic targets in ChAc that may restore neuronal function.

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“…1 and 2C). After 5 weeks of differentiation, this procedure typically generates as high as 87% of DARPP32-expressing GABAergic neurons (Ma et al, 2012). These human PSC derived medium spiny GABAergic neurons, when transplanted into the mouse striatum in which the GABAergic neurons were destroyed, were able to reconstitute the GABAergic circuits and correct the locomotive deficits (Fig.…”

Section: Differentiation Of the Lge Like Cells And The Striatal Gabaementioning

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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Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

Cited by 264 publications

References 59 publications

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification

Neuronal Dysfunction in iPSC-Derived Medium Spiny Neurons from Chorea-Acanthocytosis Patients Is Reversed by Src Kinase Inhibition and F-Actin Stabilization

Specification of functional neurons and glia from human pluripotent stem cells

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