Methods comprising apoptosis inhibitors for the generation of transgenic pigs

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Stem Cell Related Patent Number US6734015

Title:Isolation of lineage-restricted neuronal precursors
Inventors:Rao, Mahendra S.; Salt Lake City, UT, USA
Mayer-Proschel, Margot; Sandy, UT, USA
Summary:Described herein is an isolated pure population of mammalian central nervous system neuron-restricted precursor cells which are lineage restricted, are capable of undergoing self-renewal and are capable of differentiating into neurons. Central to the invention is the self-renewing restricted stem cell population which has been identified at 13.5 days of embryonic development in spinal cords, which has been shown to differentiate into multiple neuronal phenotypes, but cannot differentiate into glial phenotypes. Claims of the invention include a neuronal-restricted precursor (NRP) which expresses the highly polysialated or embryonic neural cell adhesion molecule (E-NCAM) and is morphologically distinct from neuroepithelial stem cells (NEP cells) and spinal glial progenitors derived from embryonic cells at day 10.5 in the spinal cord. The NRP cells are described as being self-renewing over multiple passages in the presence of fibroblast growth factor (FGF) and neurotrophin 3 (NT-3), and are capable of expressing a characteristic subset of neuronal epitopes. Further disclosed are the means by which cells that have been cultured in the presence of RA and the absence of FGF and NRP differentiate into GABAergic, glutaminergic, and cholinergic immunoreactive neurons, and can also be generated from multipotent NEP cells cultured from embryonic cells at day 10.5 in neural tubes. Also described are clonal analyses showing that E-NCAM immunoreactive NRP cells arise from an NEP progenitor cell that generates other restricted CNS precursors. Therapeutic methods in the treatment of neurological diseases are provided.
Abstract:A self-renewing restricted stem cell population has been identified in developing (embryonic day 13.5) spinal cords that can differentiate into multiple neuronal phenotypes, but cannot differentiate into glial phenotypes. This neuronal-restricted precursor (NRP) expresses highly polysialated or embryonic neural cell adhesion molecule (E-NCAM) and is morphologically distinct from neuroepithelial stem cells (NEP cells) and spinal glial progenitors derived from embryonic day 10.5 spinal cord. NRP cells self renew over multiple passages in the presence of fibroblast growth factor (FGF) and neurotrophin 3 (NT-3) and express a characteristic subset of neuronal epitopes. When cultured in the presence of RA and the absence of FGF, NRP cells differentiate into GABAergic, glutaminergic, and cholinergic immunoreactive neurons. NRP cells can also be generated from multipotent NEP cells cultured from embryonic day 10.5 neural tubes. Clonal analysis shows that E-NCAM immunoreactive NRP cells arise from an NEP progenitor cell that generates other restricted CNS precursors. The NEP-derived E-NCAM immunoreactive cells undergo self renewal in defined medium and differentiate into multiple neuronal phenotypes in mass and clonal culture. Thus, a direct lineal relationship exists between multipotential NEP cells and more restricted neuronal precursor cells present in vivo at embryonic day 13.5 in the spinal cord.
US Patent Website:Click Here for Full Text of Patent
Title Number:US6734015
Application Number:US1997000909435
Date Filed:04/07/1997
Date Published:11/05/2004
Assignee:University of Utah Research Foundation, Salt Lake City, UT, USA


 
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