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Su-Chun Zhang

Publications and source records attributed to Su-Chun Zhang.

14 recordsLinked to original sources
PubMed2006

Human embryonic stem cell-derived neural precursors develop into neurons and integrate into the host brain.

Whether and how in-vitro-produced human neural precursors mature and integrate into the brain are crucial to the utility of human embryonic stem (hES) cells in treating neurological disorders. After transplantation into the ventricles of neonatal immune-deficient mice, hES-cell-derived neural precursors stopped expressing the cell division marker Ki67, except in neurogenic areas, and differentiated into neurons and then glia in a temporal course intrinsic to that of human cells regardless of location. The human cells located in the gray matter became neurons in the olfactory bulb and striatum, whereas those in the white matter produced exclusively glia. Importantly, the grafted human cells formed synapses. Thus, the in-vitro-produced human neural precursors follow their intrinsic temporal program to produce neurons and glia and, in response to environmental signals, generate cells appropriate to their target regions and integrate into the brain.

Animals↗
PubMed2006

Stem cell neural differentiation: A model for chemical biology.

Stem cells can produce progenies that constitute an organism or a tissue while replenishing (renewing) themselves. The ability to produce large quantities of stage-specific cells from self-renewing stem cells in a precisely controlled manner makes it possible to dissect out complex interactions among macromolecules along development, such as early brain development at the global level. These cellular differentiation pathways also serve as templates for identifying biological effects of novel or existing chemical compounds. Thus, stem cells find their most powerful use in chemical biology, which may ultimately lead to applications in regenerative medicine.

Cell Differentiation↗
PubMed2006

Induced expression of Olig2 is sufficient for oligodendrocyte specification but not for motoneuron specification and astrocyte repression.

To dissect out interactions between the transcription factor Olig2 and other intrinsic and extrinsic factors in neural cell fate determination, we established a mouse embryonic stem (ES) cell line with induced expression of Olig2 along neural differentiation. During neuronal differentiation, both the control and Olig2-induced groups produced a similar proportion of HB9-expressing motoneurons in the presence of retinoic acid (RA) and sonic hedgehog (SHH), but both generated few motoneurons in the absence of SHH. Induced Olig2 expression did not alter the pattern of gene transcription without SHH, suggesting that Olig2 requires cooperation with RA and SHH for motoneuron specification. During glial differentiation, the Olig2-induced group generated significantly more oligodendrocytes and fewer neurons and astrocytes than the control group. This effect was not blocked by inhibition of SHH signaling, suggesting that Olig2 bypasses the need of SHH in oligodendrocyte specification. However, treatment with ciliary neurotropic factor (CNTF) markedly increased astrocyte and decreased oligodendrocyte differentiation even when Olig2 is sustained in the nuclei, suggesting that Olig2 cannot bypass the CNTF-STAT signaling to repress astrocyte differentiation.

Animals↗
PubMed2006

Neural subtype specification from embryonic stem cells.

One of the keys to using embryonic stem cells (ESCs) in brain research and potential application in neurological diseases is directed differentiation of neuronal and glial subtypes. This may be achieved by application of developmental principles in guiding cell lineage specification from naïve stem cells. Establishment of defined ESC differentiation models that recapitulate in vivo development, especially from human ESCs, will most likely provide a dynamic tool for dissecting molecular mechanisms underlying early embryonic development that is otherwise not readily obtainable. This is also a rational and realistic way of producing enriched populations of functional neurons and glia for pathological analyses as well as possible therapeutic applications.

Animals↗
PubMed2006

In vitro differentiation of neural precursors from human embryonic stem cells.

We describe a procedure for efficient and reproducible differentiation of neuroectodermal cells from human embryonic stem (ES) cells using an adherent colony culture. ES cell colonies are detached intact from the fibroblast feeder layer using dispase or collagenase. The ES cell aggregates, after 4-6 d in suspension culture, are adhered to the culture surface and form colonies of monolayer in a chemically defined medium. Under this culture condition, columnar neuroectodermal cells appear in the center of each colony and organize into neural tube-like rosettes after 14 d of differentiation culture. These neuroectodermal cells in the rosettes can be effectively isolated through differential enzymatic and adhesion treatment and the neural population accounts for at least 70% of the total differentiated progenies. Thus, our system not only provides a source of synchronized neuroectodermal cells, but also offers a paradigm to dissect mechanisms of neural induction and cell lineage specification during early human development.

Cell Adhesion↗
PubMed2005

Specification of motoneurons from human embryonic stem cells.

An understanding of how mammalian stem cells produce specific neuronal subtypes remains elusive. Here we show that human embryonic stem cells generated early neuroectodermal cells, which organized into rosettes and expressed Pax6 but not Sox1, and then late neuroectodermal cells, which formed neural tube-like structures and expressed both Pax6 and Sox1. Only the early, but not the late, neuroectodermal cells were efficiently posteriorized by retinoic acid and, in the presence of sonic hedgehog, differentiated into spinal motoneurons. The in vitro-generated motoneurons expressed HB9, HoxC8, choline acetyltransferase and vesicular acetylcholine transporter, induced clustering of acetylcholine receptors in myotubes, and were electrophysiologically active. These findings indicate that retinoic acid action is required during neuroectoderm induction for motoneuron specification and suggest that stem cells have restricted capacity to generate region-specific projection neurons even at an early developmental stage.

Biomarkers↗
PubMed2004

Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia.

Oligodendrocytes are critical for the development of the plasma membrane and cytoskeleton of the axon. In this paper, we show that fast axonal transport is also dependent on the oligodendrocyte. Using a mouse model of hereditary spastic paraplegia type 2 due to a null mutation of the myelin Plp gene, we find a progressive impairment in fast retrograde and anterograde transport. Increased levels of retrograde motor protein subunits are associated with accumulation of membranous organelles distal to nodal complexes. Using cell transplantation, we show categorically that the axonal phenotype is related to the presence of the overlying Plp null myelin. Our data demonstrate a novel role for oligodendrocytes in the local regulation of axonal function and have implications for the axonal loss associated with secondary progressive multiple sclerosis.

Alleles↗
PubMed2004

Neural differentiation from embryonic stem cells: which way?

Embryonic stem (ES) cells can in theory produce all cell types of a living organism while renewing themselves with a stable genetic background. These unique features make ES cells a favorable tool for biomedical researches as well as a potential source for therapeutic application. A first step for approaching to ES cells is the directed differentiation to cells of interest, such as the neural cell lineage. Here, we summarize the up and down sides of each category of neural differentiation protocols that have so far been used in mouse and human ES cells, and introduce an efficient and plausible method used in our laboratory for derivation of neuroectodermal cells from human ES cells. This synthesis has led to our suggestions on issues for future design of neural differentiation protocols.

Animals↗
PubMed2003

Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors.

To evaluate the functional consequence of microglial activation in vivo, oligodendroglial progenitors were transplanted into the spinal cord of Long Evans shaker, a myelin mutant rat in which myelin defects are associated with progressive microglial activation. Cells grafted into neonatal rats at the initiation of gliosis successfully myelinated axons. However, cells transplanted during peak microglial activation did not lead to myelination due to death of the grafted cells within 3 days after transplantation. Pretreatment of these animals with minocycline, a tetracycline derivative, resulted in cell survival and myelination by the grafted cells. In culture, minocycline did not affect the survival, proliferation, or differentiation of oligodendroglial progenitors. Hence, minocycline likely modulates the function of reactive glia in vivo to promote the survival and myelination of transplanted oligodendroglial progenitors.

Animals↗
PubMed2003

Embryonic stem cells for neural replacement therapy: prospects and challenges.

Injury or degeneration of the vertebrate central nervous system often disrupts neuronal circuitry that is built by projection neurons during early embryonic life. Repair of neural network through regeneration of these early-born projection neurons in adult life often fails since stem cells residing in the adult brain are generally programmed to give rise to late-born interneurons. Thus, exogenous cells are needed to rebuild the neural circuitry. Nevertheless, cell replacement in the brain remains a challenging goal because of the lack of safe and effective donor cells, as well as difficulty in remodeling the nonneurogenic adult CNS environment. Here I will concentrate on the donor side and discuss how recent advancement in stem cell technology offers hope for transplant therapy, with a focus on the potentials and hurdles of human embryonic stem cells as a sustainable source.

Animals↗
PubMed2002

Inhibition of autoimmune encephalomyelitis by a tetracycline.

We have explored the use of minocycline, a tetracycline with antiinflammatory properties, to treat chronic relapsing-remitting experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Therapeutic treatment with minocycline dramatically suppresses ongoing disease activity and limits disease progression. Disease suppression is associated with immune deviation in the periphery and with suppression of the inflammatory cascade in the central nervous system. This association is demonstrated by inhibition of microglial activation and metalloproteinase-2 expression, which results in a concomitant decrease in inflammation and demyelination. As an established antiinflammatory drug with neuroprotective properties, minocycline may provide a novel therapeutic agent for relapsing-remitting multiple sclerosis.

Animals↗
PubMedDate not supplied

Directed differentiation of dopaminergic neuronal subtypes from human embryonic stem cells.

How dopamine (DA) neuronal subtypes are specified remains unknown. In this study we show a robust generation of functional DA neurons from human embryonic stem cells (hESCs) through a specific sequence of application of fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH). Treatment of hESC-derived Sox1+ neuroepithelial cells with FGF8 and SHH resulted in production of tyrosine hydroxylase (TH)-positive neurons that were mostly bipolar cells, coexpression with gamma-aminobutyric acid, and lack of midbrain marker engrailed 1 (En1) expression. However, FGF8 treatment of precursor cells before Sox1 expression led to the generation of a similar proportion of TH+ neurons characteristic of midbrain projection DA neurons with large cell bodies and complex processes and coexpression of En1. This suggests that one mechanism of generating neuronal subtypes is temporal availability of morphogens to a specific group of precursors. The in vitro-generated DA neurons were electrophysiologically active and released DA in an activity-dependent manner. They may thus provide a renewable source of functional human DA neurons for drug screening and development of sustainable therapeutics for disorders affecting the DA system.

Animals↗