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 µ-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."
In the June 26th online advance publication of Developmental Cell, J. Vilarras-Blasi et al. from the Center for Research in Agricultural Genomics (Barcelona, Spain) published their study results on the molecular mechanism(s) in which stem cells in the plant root niche regulate quiescence. The investigators identified a R2R3-MYB transcription factor, (BRAVO/Brassinosteroids at Vascular and Organizing Center) which acts as a repressor of cell division of the Brassinosteroid pathway in the quiescent center (QC) of the root. Ectopic expression of BRAVO restricts root growth and counteracts BR-mediated cell division in order to protect the root stem cell niche. Additionally, the Brassinosteroid (BR)-regulated transcription factor BES1 (BRI1-EMS Suppressor 1) interacts and represses BRAVO in vivo which serves as a switch for modulating QC divisions at the root stem cell niche. The authors concluded that their results "define a mechanism for BR-mediated regulation of stem cell quiescence in plants."
In the June 22nd online early publication of Nature Cell Biology, G. Whissell et al. from the Institute for Research in Biomedicine (Barcelona, Spain) published their study observations on the aberrant activation of WNT signaling and subsequent loss of BMP signals which results in initiating colorectal cancer (CRC). The investigators conducted a screen to determine which genes were required for maintaining a cancer-initiating stem cell phenotype. The experimental results demonstrated that the zinc-finger transcription factor GATA6 as a key regulator of WNT and BMP signaling in CRCs. GATA6 was shown to drive the expression of LGR5 in adenoma stem cells concomitant with restricting BMP signaling in differentiated tumor cells. Genetic deletion of GATA6 increases BMP signaling and block tumor stem cells from self-renewing. Additionally, the researchers noted that GATA6 competes with β-catenin/TCF-4 in binding to the BMP4 distal regulatory region resulting in increased susceptibility to the development of CRC. Thus, the authors concluded that "GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signaling required for tumor stem cell expansion."
In the June 18th online early publication of Cell Stem Cell, B. O. Zhou et al. from the University of Texas Southwestern Medical Center reported their study results on identifying a subpopulation of mesenchymal stromal cells (MSCs) expressing the Leptin Receptor (LepR) which in vitro and in vivo form adipocytes, osteocytes, and chondrocytes. The investigators reported that in the adult bone marrow, 0.3% of the LepR+ cells accounts for 94% of the CFU-Fs. Fate mapping analyses revealed that postnatal "LepR+ cells give rise to most of the bone and adipocytes formed in adult marrow." LepR+ cells were shown to be quiescent in the adult marrow. However, LepR+ cells are activated and proliferate in response to injury and subsequently involved in bone regeneration. The authors concluded from their study observations that "LepR+ cells are major source of bone and adipocytes in adult marrow."