Differentiation potential of histocompatible parthenogenetic embryonic stem cells.

Division of Pediatric Hematology/Oncology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 07/2007; 1106:209-18. DOI: 10.1196/annals.1392.011
Source: PubMed

ABSTRACT Embryonic stem cells (ESCs) hold unique promise for the development of cell replacement therapies, but derivation of therapeutic products from ESCs is hampered by immunological barriers. Creation of HLA-typed ESC banks, or derivation of customized ESC lines by somatic cell nuclear transfer, have been envisioned for engineering histocompatible ESC-derived products. Proof of principle experiments in the mouse have demonstrated that autologous ESCs can be obtained via nuclear transfer and differentiated into transplantable tissues, yet nuclear transfer remains a technology with low efficiency. Parthenogenesis provides an additional means for deriving ESC lines. In parthenogenesis, artificial oocyte activation initiates development without sperm contribution and no viable offspring are produced in the absence of paternal gene expression. Development proceeds readily to the blastocyst stage, from which parthenogenetic ESC (pESC) lines can be derived with high efficiency. We have recently shown that when pESC lines are derived from hybrid mice, early recombination events produce heterozygosity at the major histocompatibility complex (MHC) loci in some of these lines, enabling the generation of histocompatible differentiated cells that can engraft immunocompetent MHC-matched mouse recipients. Here, we explore the differentiation potential of murine pESCs derived in our laboratory.

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    ABSTRACT: Parent of origin imprints on the genome have been implicated in the regulation of neural cell type differentiation. The ability of human parthenogenetic (PG) embryonic stem cells (hpESCs) to undergo neural lineage and cell type-specific differentiation is undefined. We determined the potential of hpESCs to differentiate into various neural subtypes. Concurrently, we examined DNA methylation and expression status of imprinted genes. Under culture conditions promoting neural differentiation, hpESC-derived neural stem cells (hpNSCs) gave rise to glia and neuron-like cells that expressed subtype-specific markers and generated action potentials. Analysis of imprinting in hpESCs and in hpNSCs revealed that maternal-specific gene expression patterns and imprinting marks were generally maintained in PG cells upon differentiation. Our results demonstrate that despite the lack of a paternal genome, hpESCs generate proliferating NSCs that are capable of differentiation into physiologically functional neuron-like cells and maintain allele-specific expression of imprinted genes. Thus, hpESCs can serve as a model to study the role of maternal and paternal genomes in neural development and to better understand imprinting-associated brain diseases.
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    ABSTRACT: Cell replacement strategies hold great promise for the treatment of central nervous system injuries and degenerative diseases. The advancement of stem cell therapies has proven to be a viable therapeutic approach to limit secondary degeneration and restore neuronal circuitry at the site of injury. Cell replacement strategies confer phenotype-specific and neurotrophic benefits to the surrounding tissue; however, the mechanisms of transplant-mediated repair are unique to each transplant population. Here, we review stem cell-based therapies for spinal cord injury and disease, involving a number of stem cell derivates. We discuss the mechanisms by which each of these populations exert their affects and briefly discuss phenotype-specific cell replacement in these models.
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