Notch Signaling-Mediated Neural Lineage Selection Facilitates Intrastriatal Transplantation Therapy for Ischemic Stroke by Promoting Endogenous Regeneration in the Hippocampus
Abstract:Acquisition of highly efficient neural differentiation based on understanding of initial lineage commitment of human embryonic stem (hES) cells remains a challenge. This study describes a simple three-stage protocol to induce hES cells into neural lineage cells using a 2-week coculture with murine bone marrow stromal cell (BMSC) PA6 followed by a 2-week propagation culture in PA6-conditioned medium and an additional 2-week selection culture in chemically defined neurobasal medium. This protocol generated a relatively high yield of neural lineage cells without mesodermal and endodermal lineage cell contamination. Notably, we demonstrated that PA6 coculture can significantly enhance the expression level of Notch signaling components and promote neural lineage entry of hES cell derivatives. Manipulation of Notch signaling can boost or suppress neural differentiation of hES cell derivatives, suggesting that Notch signaling may underlie the PA6-mediated neural induction. In vivo studies demonstrated that derived neural cells could improve the cognitive function of ischemic stroke rats. Intrastriatal human neural cell grafts were noted to migrate to damaged cerebral regions, enhance basic fibroblast growth factor production in the hippocampus, and restore the pyramidal neuron density and morphology in the hippocampal CA1 region, although only a small number of human donor cells were present in the hippocampus, suggesting that donor cells can boost hippocampal reconstruction by promoting the endogenous regeneration process. These findings demonstrate a pivotal role for Notch in hES cell fate determination and that manipulation of Notch signaling is therefore likely to be a key factor in taking command of hES cell lineage choice. This study suggested the potential of utilizing PA6 coculture to imitate the embryonic niche for hES cell neural induction via Notch signaling and a high application potential of BMSC-involved protocol, which can yield a whole lineage of human neural cells to promote endogenous regeneration in the hippocampus upon transplantation for potential therapy of ischemic stroke.
Document Type: Research Article
Publication date: 2014-02-14
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- Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.