Showing papers by "Gabriel Nistor published in 2011"

Human Motor Neuron Progenitor Transplantation Leads to Endogenous Neuronal Sparing in 3 Models of Motor Neuron Loss

Abstract: Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

Derivation of High Purity Neuronal Progenitors from Human Embryonic Stem Cells

Abstract: The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use.

Equivalence of Conventionally-Derived and Parthenote-Derived Human Embryonic Stem Cells

Abstract: BackgroundAs human embryonic stem cell (hESC) lines can be derived via multiple means, it is important to determine particular characteristics of individual lines that may dictate the applications to which they are best suited. The objective of this work was to determine points of equivalence and differences between conventionally-derived hESC and parthenote-derived hESC lines (phESC) in the undifferentiated state and during neural differentiation.Methodology/Principal FindingshESC and phESC were exposed to the same expansion conditions and subsequent neural and retinal pigmented epithelium (RPE) differentiation protocols. Growth rates and gross morphology were recorded during expansion. RTPCR for developmentally relevant genes and global DNA methylation profiling were used to compare gene expression and epigenetic characteristics. Parthenote lines proliferated more slowly than conventional hESC lines and yielded lower quantities of less mature differentiated cells in a neural progenitor cell (NPC) differentiation protocol. However, the cell lines performed similarly in a RPE differentiation protocol. The DNA methylation analysis showed similar general profiles, but the two cell types differed in methylation of imprinted genes. There were no major differences in gene expression between the lines before differentiation, but when differentiated into NPCs, the two cell types differed in expression of extracellular matrix (ECM) genes.Conclusions/SignificanceThese data show that hESC and phESC are similar in the undifferentiated state, and both cell types are capable of differentiation along neural lineages. The differences between the cell types, in proliferation and extent of differentiation, may be linked, in part, to the observed differences in ECM synthesis and methylation of imprinted genes.

Derivation of Oligodendrocyte Progenitor Cells from Human Embryonic Stem Cells

Abstract: The directed differentiation of human pluripotent stem cells into specific, determined, and high-purity cell types can provide a means to study the cellular and molecular mechanisms of development and to generate cells for potential therapeutic applications. The ability to derive homogeneous cell populations obviates the need for transgene expression or cell sorting methods and can improve selection efficiency, lineage differentiation, cell viability, and clinical utility. Compared to undifferentiated pluripotent stem cells, high-purity cell phenotypes for clinical therapeutic strategies are expected to enhance engraftment, potentiate clinical efficacy, and decrease the risk of adverse effects such as dedifferentiation or teratoma formation. Clinical interest in the derivation of oligodendrocyte progenitor cells from pluripotent stem cells is based on research that demonstrates the effectiveness of progenitor cell transplants to improve outcomes after spinal cord injury. Here, we describe a protocol to generate oligodendroglial lineage-specific cells in high purity from human embryonic stem cells.

Oligodendrocyte derived from human embryonic stem cell for remyelination and treatment of spinal cord injury

Abstract: PROBLEM TO BE SOLVED: To provide populations of neural cells bearing markers of glial cells, such as oligodendrocytes and the precursor cells thereof. SOLUTION: The cell populations are generated by differentiating pluripotent stem cells such as human embryonic stem cells under conditions that promote enrichment of cells with the desired phenotype or functional capability. The cell populations bearing markers of oligodendrocyte precursor cells can be produced by using various combinations of differentiation factors and mitogens can be used to produce cell populations. Upon further differentiation, complex projections characteristic of mature oligodendrocytes are formed. The cells are capable of forming myelin sheaths, and can be used for therapeutic improvement of function of the central nervous system. COPYRIGHT: (C)2011,JPO&INPIT