In the August 26th online advance publication of PNAS, Y. Jiang and J. Hsieh from the University of Texas Southwestern Medical Center reported their study on the mechanism(s) in which the histone deacetylase 3 (HDAC3) regulates maintenance and proliferation of neural stem/progenitor cells (NSPC) in mouse adult hippocampus. The investigators demonstrated that HDAC3, a histone-modifying enzyme, is required for proliferation of adult NSPCs. In Hdac3 conditional knockout (cKO) mice, there was observed "a defect in cell cycle progression through gap2/mitosis (G2/M) but not S phase." The experimental results suggested that HDAC3 controls G2/M progression through posttranslational stabilization of the G2/M cyclin-dependent kinase 1 (CDK1). The authors concluded from their study results that "HDAC3 plays a critical role in NSPC proliferation and suggest that strategies aimed at pharmacological modulation of HDAC3 may be beneficial for tissue regeneration and controlling tumor cell growth."
In the August 6th advance online publication of Nature, L. Pan et al. from the Stowers Institute for Medical Research (Kansas City, MO) reported their study results on the intrinsic factors which determine stem cell self-renewal and differentiation. The investigators used Drosophila melanogaster ovaries to determine the mechanism in which germline stem cells (GSCs) switch from a state of self-renewal to differentiation. The experimental results revealed that the differentiation factor, Bam, controls the functional switch of the COP9 complex from self-renewal to differentiation by way of protein competition. The COP9 complex consists of eight Csn subunits and the complex is required intrinsically for GSC self-renewal. It was noted that other Csn proteins are required for GSC progeny differentiation, with the exception of Csn4. Bam was found to mediate Csn4 sequestration from the COP9 complex via protein competition and inactivates the self-renewing function of COP9 concomitant with other Csn proteins promoting GSC differentiation. The authors concluded from their experimental results that "protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation" may be an important mechanism in which stem cells in other tissue systems uses as a switch from self-renewal to differentiation.
In the June 15th issue of Neural Regeneration Research, D. Zou et al. from the First Affiliated Hospital of China Medical University (Jinhua, China) reported their study results on overexpression of microRNA-124 (miR-124) in bone marrow-derived mesenchymal stem cells (BMSCs) and its ability to differentiate into neural stem cells. The investigators transduced BMSCs with a lentiviral vector overexpressing miR-124. The experimental data revealed an increased in intracellular expression levels of β-III tubulin (neuronal early marker) and microtubule -associated protein-2 as well as a "reduction of apoptosis induced by oxygen and glucose deprivation." The researchers reported that post-transplantation of the transfected BMSCs into rat with spinal cord injury resulted in a significant increase in the number of cells staining positive for the neuronal marker, neurofilament-200. Functional assays using the Basso-Beattie-Bresnahan score showed a substantial improvement in motor function in the hind limb of rats. The authors concluded from their experimental findings that their results "suggest that miR-124 plays an important role in the differentiation of bone marrow-derived mesenchymal stem cells into neurons."
In the July 17th online early edition of Cell Stem Cell, P. Charbord et al. INSERM (Villejuif, France) reported their experimental findings on the molecular requirements for supporting the hematopoietic stem/progenitor cell (HSPC) niches. The investigators conducted transcriptome meta-analysis on a panel of six HSPC stromal cell lines from embryonic and adult tissues that were either supportive or less-supportive of the hematopoietic niche. The experimental data 481 mRNAs transcripts and 17 microRNAs in a modular network indicative of paracrine signaling and HSPC support by stromal cells without cell-cell contact. Functional studies in zebrafish embryos confirmed the gene set of niche support which consisted of known HSPC regulators such as Pax9 and Ccdc80. The authors concluded that their study results "identified the core molecular network required for HSPC support."
In the July 17th online edition of Cell Reports, M. Foronda et al. from the Spanish National Cancer Research Centre (CNIO) published heir experimental results on dissecting the regulatory of Sox4 expression in normal tissue replacement, cancer, and aging. In mammals, Sox4 expression is restricted to the development of embryonic tissues and some adult tissues such as lymphoid, pancreas, intestine, and skin. The investigators were able to generate mice with reduced whole body expression of Sox4. In Sox4-deficient mice, they were found to be resistant to cancer with accelerated aging. However, aberrant Sox4 expression was linked to malignant transformation and metastasis in several types of cancer. Conditional deletion of Sox4 in stratified epithelial leads to stem cell quiescence and skin damage concomitant with a "downregulation of the cell cycle, DNA repair, and activated hair follicle stem cell pathways." The researches performed expression analysis and found Sox4 to be involved in the β-catenin/Wnt signaling pathway during hair follicle stem cell activation. The authors concluded from their study results that Sox4 has an important role "in regulating adult tissue homeostasis and cancer."
In the July 10th online advanced publication of Cell Stem Cell, M. Hanoun et al. from Albert Einstein College Medicine reported their study results on the effects of acute myelogenous leukemia stem cells the bone marrow microenvironment. Using a AML mouse model (MLL-AF9), the investigators found that neuropathy of the sympathetic nervous system (SNS) promotes leukemic bone marrow infiltration. AML disease progression disrupts the SNS nerves and the quiescent Nestin+ cells within the bone marrow niche. The altered bone marrow microenvironment leads to expansion of mesenchymal stem and progenitor cells (MSPCs) which results in enhanced differentiation towards osteoprogenitors. AML also results in a reduction in the number of NG2+ periarteriolar niche cells which regulate the HSC niche. The experimental data also revealed that neuropathy of the SNS promotes AML by adrenergic signaling through the β3 adrenergic receptor on the stromal cells. The authors concluded that their study results "indicate that sympathetic neuropathy may represent a mechanism for the malignancy in order to co-opt the microenvironment and suggest separate mesenchymal niche activities for malignant and healthy hematopoietic stem cells in the bone marrow."
In the June 25th online advance publication of Stem Cells, C. Xu et al. from the University of Minnesota Medical School reported their study results on how addictive drugs such as morphine regulates adult neurogenesis. Morphine has been shown to induce hippocampal neural progenitor cells (hNPCs) to differentiate into astrocytes. The investigators found that this effect is mediated by the Prox1/Notch1 pathway and blocked by the -receptor antagonist, Cys2-Tyr3-Orn5-Pen7-amide. Over-expression of Prox1 siRNA was shown to upregulate Notch1 levels and potentiate the morphine-induced lineage differentiation of the hNPCs to astrocytes. The experimental data revealed that the effect of morphine on hNPC lineage changes was correlated with Prox1 transcript levels and an increase in miR-181a levels. Over-expression of miR-181a was found to mimic reduced Prox1 levels concomitant with an increase in Notch1 levels and enhanced differentiation of hNPCs into astrocytes. The authors concluded from their study results that "by modulating Prox1/Notch1 activities via miR-181a, morphine influences the fate of differentiating hNPCs differentiation and therefore the ultimate quantities of mature neurons and astrocytes."
In the June 5th issue of Cell, D. Yinlamai et al. from Boston Children's Hospital reported their study results on Hippo signaling and its role in regulating cell fate. With lineage tracing, clonal, and organoid culture analyses, the investigators found Hippo signaling is differentially regulated in hepatocytes. Hippo signaling is essential for maintaining hepatocytes in a differentiated state. The experimental data also revealed in vivo that Hippo inactivation resulted in dedifferentiation of adult hepatocytes into hepatic progenitors at very high efficiencies. The progenitors were shown to self-renew as well as having the capacity to engraft at the single cell level. The Hippo transducer, YAP, was shown to control liver cell fate. Additionally, the experimental data revealed "unprecedented levels of phenotypic plasticity in mature hepatocytes." The authors noted that NOTCH signaling pathway as an important functional downstream effector of YAP.
In the June 30th online advance publication of PNAS, R.-Z. Lin et al. from the Massachusetts Institute of Technology reported their study results on the role of endothelial colony-forming cells (ECFCs) in modulating the regenerative potential of human mesenchymal stem cells (MSCs) following engraftment. With ECFCs and its vasculogenic properties, the investigators conducted experiments to determine whether ECFCs are able to function as paracrine mediators. The investigators used two xenografts models of human MSCs and cord blood-derive ECFCs co-transplanted into immunodeficient mice. MSCs were isolated from white adipose tissue and bone marrow aspirates. The experimental results demonstrated that ECFCs secreted paracrine factors such as platelet-derived growth factor BB (PDGF-BB) which modulates platelet-derived growth factor receptor (PDGFR)-β signaling. The researchers found that co-transplantation with ECFCs enhanced MSC engraftment by "reducing early apoptosis and preserving stemness-related properties of PDGFR-β+ MSCs" as well as repopulating secondary grafts. The in vivo data revealed the transplanted MSC possessed a fate-restricted potential with differentiation were exclusively along adipogenic and osteogenic lineages. The authors concluded that their "work demonstrates that blood-derived ECFCS can serve as paracrine mediators and regulate the regenerative potential of MSCs via PDGF-BB/PDGFR-β signaling."
In the June 23rd online early edition of PNAS, S. Jamaladdin et al. from the University of Leicester (UK) reported their study results on the role of histone deacetylase 1 and 2 (HDAC1/2) in regulating gene expression in embryonic stem cells (ESCs). HDAC 1/2 are core catalytic corepressor complexes that modulate gene expression through chromatin modification. The investigators generated a ESC line in which HDAC1/2 can be simultaneously inactivated. The experimental results demonstrated that loss of HDAC1/2 resulted in a loss in cell viability concomitant with abnormal mitotic spindles and chromosome segregation. In the double knockout of Hdac1/2 approximately 2,000 genes are dysregulated. The researchers also detected a decrease in the expression of pluripotent transcription factors , Oct4, Nanog, Esrrb, and Rex1 with the loss of HDAC1/2. The researchers also found HDAC1/2 activity is "regulated through binding of an inositol tetraphosphate molecule (IP4)." IP4 was shown to be sandwiched between HDAC and its cognate corepressor. Mutations that abolish IP4 binding reduce the activity of HDAC in vivo. The authors concluded that their "data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key transcription factors."