In the May 20th online early edition of PNAS, J. Chang et al. from the University of California, Los Angeles School of Dentistry published their study results on the effects of proinflammatory cytokines on inhibiting osteogenic differentiation of mesenchymal stem cells (MSCs). The invesitgators found that both proinflammatory cytokines "TNF and IL-17 stimulated the IkB kinase (IKK)-NF-kB impaired osteogenic differentiation of MSCs." Conversely, inhibiting activation of the IKK-NF-kB signaling pathway enhanced osteogenesis and subsequent MSC-mediated bone formation. Additionally, activation of IKK-NF-kB signaling pathway resulted in ubiquination and degradation of b-catenin via Smurf1 and Smurf2 induction. A small molecule inhibitior of IKK, IKKVI, enhanced osteogenic differentiation of MSCs in vitro and in vivo delivery promoted craniofacial bone regeneration. The authors concluded from their study results that " targeting IKKNF may have dual benefits in enhancing bone regeneration and repair and inhibiting inflammation."
In the May 9th online early publication of Cell Stem Cell, E. Apostolou et al. Massachusetts General Hospital reported their study results on genome-wide, pluripotency network involving the Nanog promoter. The experimental results revealed that the Nanog promoter formed a pluripotent chromatin interactome. The pluripotency-specific network is rearranged during differentiation and restored in induced pluripotent stem cells (iPSCs). In embryonic stem cells (ESCs), Nanog promoter interaction were maintained by binding of Mediator and cohesion in the chromatin. When these proteins were depleted the interactome acquired a differentiation-specific pattern prior to transcriptional and phenotypic changes. The investigators also noted that Nanog promoter interactions during reprogramming preceded increased gene expression of pluripotent-associated genes. The authors concluded from their observations that their experimental results describe "a complex, pluripotency-specific chromatin 'interactome' for Nanog and suggest a functional role for long-range genomic interactions in the maintenance and induction of pluripotency."
In the April 23rd online of PNAS, J. Xia et al. from The Scripps Research Institute reported their study results on using antibody agonists for transdifferentiating human stem cells. Antibody agonists for granulocyte colony stimulating factor were selected from intraccellular combinatorial libraries. With "near neighbor" approach, antibody agonists were selected on their ability to cointegrate with the target receptor into the plasma membranes of reporter cells. The near neighbor format allows for the interactions between receptors and ligands which provides for the antibody to behave in an autocrine fashion. The researchers found that isolated agonist antibodies induced transdifferentiation of bone marrow-derived CD34+ into neural progenitors. The authors suggested from their experimental data that "transdifferentiation by agonists is different from commonly used methods because initiation is agenetic."
In the April 22nd online early edition of PNAS, Y.-C. Chang et al. from Johns Hopkins School of Medicine reported their study results on using Drosophila follicle stem cells (FSCs) as a model for delineating the molecules and mechanisms that governs cell=fate specifications in adult stem cells. The investigators were able to identify Castor (Cas) nuclear protein which is expressed in early in FSCs and early follicle cell precursors. However, castor expression is restricted to differentiated polar and stalk cell fate specification during oogenesis. The study results revealed that Cas was required for FSC maintenance. Cas was also shown to function in a genetic circuit with both hedgehog and eyes absent (Eya) genes. Polar and stalk cell fate is repressed by Eya inhibiting Cas expression. Additionally, hedgehog signaling represses Eya which allows Cas expression in polar and stalk cells. The authors concluded from their study results that by using a Drosophila FSC model they were able to identify a marker for cell fates in adult stem cells as well as as gaining insight into the "molecular and cellular mechanisms by which FSC progeny diverge into distinct fates."
In the April 15th online early edition of PNAS, A. N. Bowman et al. from Stanford University reported their study results on the role of Wnt/b-catenin signaling pathway during the developmental continuum in embryonic to postnatal neural stem cells. With tamoxifen-inducible Cre in a Axin2 mouse strain, the investigators conducted lineage tracing experiments to determine "the developmental fate of Wnt/b-catenin responsive cells." The study data revealed that as early as day 8.5 Axin2 positive embryonic cells eventually gave rise to the adult neural stem cells in the subventricular zone. On E12.5 the embryonic labeled cells' progeny contribute to the neural stem cells in both the subventricular zone and dentate gyrus of the hippocampus. Additionally, the researchers reported that the Axin2+ cells gave rise to persistent long-lived, Wnt/b-catenin-responsive stem cells in both subventricular zone and dentate gyrus of the postnatal brain. The authors concluded from their experimental observations "the continued importance o f Wnt/3/4 - catenin signaling for neural stem and progenitor cell formation and function throughout developmental time."
In the April 9th online early publication of PNAS, N. Ikegaki et al. from the University of Illinois College of Medicine published their study results in which transient treatment of a neuroblastoma (NB) cell line with epigenetic modifiers give rise to cells with stem-like properties (expression of stem cell markers) and open chromatin structures. The investigators designated epigenetic conversion of NBs into a stem cell phenotype as induced cancer stem cells (iCSCs). In vivo, the iCSCs xenografts formed highly aggressive metastatic tumors in mice. The tumors had the "histologic appearance of undifferentiated large-cell NBs (LCN)---the most aggressive and deadly form of NB in humans." The iCSC xenografts expressed high level of CXCR4 (stem cell marker) and MYC/MYCN. The authors concluded that their experimental observations suggest "that NB cells with large and vesicular nuclei, representing their open chromatin structure, are indicative of stem cell-like tumor cells and that epigenetic changes may have contributed to the development of these most malignant NB cells."
In the April 8th online early publication of PNAS, Y. Wei et al. from Shanghai Medical College of Fudan University (China) reported http://www.pnas.org/content/early/2013/04/04/1217002110.abstract.html?etoc their experimental results on the role of the surface CD133 in modulating glioma stem cell (GSCs) behavior. The investigators reported that phosphorylation of tyrosine-828 residue in the cytoplasmic C-terminal domain results in direct interaction of p85 (regulatory subunit of CD133) and preferential activation of the PI3K/protein kinase B (Akt) signaling pathway in glioma stem cells but not in normal non-stem cells. When CD133 expression is knocked down, the PI3K/Akt signaling pathway is inactive which results in a reduction in self-renewal and tumorigenicity of GSC. Wild type CD133+ GSCs can rescue the inhibitory effects of knockdown CD133. The researchers observed that the level of phosphorylation of the tyrosine-82 residue of CD133 and PI3K/Akt signaling correlates with histopathological grading of glioma tissue samples.
In the February 14th early online publication of Cell Stem Cell, I. Beerman et al. from Boston Children's Hospital published their study results on the relationship between age-associated hematopoietic stem cell (HSC) decline and DNA methylation. The investigators found that site-specific alterations of the DNA accompany HSC aging. Analyzing the DNA methylome, alteration of DNA methylation at specific genomic regions targets genes associated with hematopoietic lineage concomitant with altering HSC potential. The targeted genes are expressed in downstream progenitor and effector cells. Additionally, the researchers found that age-associated HSC decline in potential, replicative limits, and DNA methylation are dependent upon the proliferative history of HSCs. Forced proliferation and aging give rise to DNA hypermethylation of genes regulated by the Polycomb Repressive Complex 2 (PRC2). The authors concluded from their study observations that "epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging."
In the February 15th online early edition of PNAS, A. Insinga et al. from European Institute of Oncology (Milan, Italy) published their experimental observations on the mechanisms which allow adult stem cells to resist DNA damage-induced apoptosis or senescence while suppressing tumorigensis. The investigators found that irradiating hematopoietic and mammary stem cells upregulates the cell cycle inhibitor, p21, and prevents p53 activation concomitant with entry into the cell cycle and symmetric self-renewing divisions. The experimental results also demonstrate that p21 activates DNA repair and limits the accumulation of damage DNA as well as "self-renewal exhaustion." The researchers found that stem cells with moderate DNA damage along with an inability to self-renew persisted after irradiation. The authors concluded from their findings that "stem cells have evolved a unique, p21-dependent response to DNA damage that leads to their immediate expansion and limits their long-term survival."
In the February 4th early online edition of PNAS, F. Foijer et al. from the Wellcome Trust Sanger Institute (UK) published the results of their study on the effects of spindle assembly checkpoint (SAC) factors on both mouse epidermal and hair follicle bulge stem cells. SAC gene expression is essential for chromosome segregation during mitosis and preventing aneuploidy in normal cells. The investigators used conditional knockout (KO) mice of Mad2 gene to inactivate the SAC signaling pathway. SAC inactivation was found to be tolerated by interfollicular epidermal cells and depleted hair follicle bulge stem cells in the Mad2-deficient mouse. One month after birth, the KO mice had normal epidermal development, but without hair. Mad2-deficient epidermal cells were aneuploidy which was confirmed by abnormal transcription of metabolic genes. Hair follicle bulge stem cells were completely absent in the Mad2-deficient mice. The authors concluded that their "data demonstrate that different cell lineages within a single tissue respond differently to chromosome instability: some proliferating cell lineages can survive, but stem cells are highly sensitive."