In the November 8th online early publication of Stem Cells, X. Li et al. from Massachusetts General Hospital reported their experimental results on the role of the Krüppel-like transcription factor ZBP-89 (Zfp148) in hematopoiesis of adult mouse hematopoietic stem/progenitor cells (HSPCs). The investigators performed conditional deletion of ZBP-89 in HSPCs which results in anemia and thrombocytopenia; particularly, after chemically induced erythro/megakaryopoietic stress. Additionally, bone marrow transplantation of ZBP89-/- HSPC resulted in myeloid-to-B lymphoid switch in the bone marrow recipients. In vitro experiments demonstrated that myeloid-to-B lymphoid switch is associated with the up-regulation of PU.1 and down-regulation of SCL/Tal1 and GATA-1 in ZBP-89 deficient cells. The researchers further demonstrated that ZBP-89 is a direct repressor of PU.1 and activator of SCL/Tal1 and GATA-1. The authors concluded that their experimental results demonstrated the role of "ZBP-89 in regulating stress hematopoiesis in adult mouse bone marrow."
In the October 28th online edition of PNAS, F. Wang et al. from Harvard Medical School reported their study results on adipocyte master regulator peroxisome proliferator-activator receptor gamma (PPARg) and the effects of its loss in (PPARg FKO) knockout mouse model . By age 3 months in PPARg FKO mice, the investigators reported that was almost no visible brown and white adipose tissue concomitant with enlarged pancreatic islets, massive fatty livers, and elevated levels of blood glucose and serum insulin (insulin resistance). The PPARg FKO mice also showed "delayed hair coat formation due to the absence of dermal fat, disrupted mammary gland development, loss of mammary fat pads, and high bone masse with loss of bone marrow fat." The authors concluded from their study results that their "data reveal the necessity of fat PPARg adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues."
In the November 6th online publication of PNAS, H. Ohno et al. from the University of California, San Francisco published their study results on the molecular switch regulating differentiation of Myf5+ dermotomal precursors into brown adipocytes. The experimental results revealed that the euchromatic histone-lysine N-methyltransferase 1 (EHMT1) is essential for the PR domain containing protein 16 (PRDM16) transcriptional complex for controlling brown adipose cell fate. Loss of EHMT1 in brown adipocytes resulted in the loss of brown fat and induction of muscle differentiation in vivo. The experimental results suggested that EHMT1 modulates demethylation of H3K9me2 and 3 at the promoter region for muscle differentiation. The investigators also noted that "EHMT1 expression positively regulates the BAT (brown adipose tissue)-selective thermogenic program by stabilizing the PRDM16 protein. Notably, adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity and systemic insulin resistance." The authors concluded that "EHMT1 is an essential enzymatic switch that controls brown adipose cell fate and energy homeostasis."
In the November 4th online early publication of PNAS, B. E. Rockich et al. from the University of Michigan School of Medicine published their study results on the role of Sox9 transcription factor during lung morphogenesis. The investigators found that Sox9 is expressed at the distal tips of the branching epithelium and is downregulated by day 16.5 concomitant with the onset of terminal differentiation of type 1 and type 2 alveolar cells. With genetic gain- and loss-of-function assay for epithelial cells, the experimental results demonstrated that Sox9 controls several aspects of lung branching. Defined levels of Sox9 can tip the balance to either proliferation or to differentiation of epithelial tip progenitor cells. Additionally, loss of Sox9 results in "extracellular matrix defects, cytoskeleton disorganization, and aberrant epithelial movement" in the developing lung. Interestingly, the researchers noted that Sox9 expression is not regulated by Wnt/b-catenin signaling in the lungs. The authors conclude from their study observations that "Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix."
In the October 24th online early publication of PNAS, C. Perdomo et al. from Boston University School of Medicine reported their experimental results on mircoRNAs' role in modulating changes in the airway associated with lung cancer induced by smoking. The investigators identified microRNA 4423 (miR-4423) as primate-specific microRNA expressed in the mucocillary epithelium of the lung. In vitro, miR-4423 induces bronchial epithelial cells to differentiate into mucocillary epithelium. Additionally, overexpression of miR-4423 increases the number of cilliated cells in vitro. Conversely, miR-4423 expression in lung tumors were reduced, particularly, in the mainstem bronchus of smokers with lung cancer. In a mouse xengraft model, ectopic expression of miR-4423 significantly decreases the size of the tumors. The researchers noted that overexpression of miR-4423 induces a gene expression profile reflecting a differentiated pattern of the airway epithelium as well as reverses the expression of altered genes in lung cancer. The authors concluded from their study observations that "miR-4423 is a regulator of airway epithelium differentiation and that the abrogation of its function contributes to lung carcinogenesis."
In the October 30th online early publication of PNAS, R. M. George et al. from Arizona State University published their study results on the adaptor protein, Numb, in regulating muscle mass (Myostatin). Numb is a regulator of cell proliferation and differentiation in satellite cells during muscle repair in mice. The investigators used two different genetic approaches (conditional mutations) to determine the role of Numb in muscle regeneration in response to an injury. Ablation of Numb impaired muscle regeneration and, in vitro, myofiber cultures demonstrated a lack of satellite and stem cell proliferation concomitant with upregulation of Myostatin and p21. Additionally, overexpression of Numb and transfection of Myostatin-specific siRNA were shown to rescue the proliferation effect in Numb-deficient satellite cells. Thus, overexpression of Numb in satellite cells inhibited Myostatin expression. The authors conclude from their study results that their "data indicate an unique function for Numb during the initial activation and proliferation of satellite cells in response to muscle injury."
In the October 22nd online early publication of PNAS, T. Grigoryan et al. Max Delbruck Center for Molecular Medicine (Berlin, Germany) published their study results on delineating the underlying mechanism by which immature, murine Schwann cells (SCs) after birth segregate large axons from bundles through a process called "axonal radial sorting." The investigators found that Wnt signaling played a critical role in regulating axonal sorting. In mice carrying a b-catenin mutation, loss of function resulted in a delay of axonal sorting; conversely, gain of function mutations accelerated axonal sorting. The researchers also reported that abnormal process extension, differentiation, and aberrant cell cycle exit of the SCs accompanied the sorting deficit. In vitro, the cultured SCs down-regulation of Wnt/b-catenin signaling inhibits cell spreading and lamellipodia formation, whereas up-regulated Wnt/b-catenin signaling promoted spreading and lamellipodia formation.
In the October 29th online early publication of Stem Cells, J. Macas et al. from Frankfurt University Medical School reported their study results on migration pattern of neuronal progenitor cells (NPCs) toward brain tumors (high-grade astrocytomas) in humans. The investigators analyzed neurosurgical resections of tumor-parenchyma interface for the presence of NSA-NCAM-positive NPCs. The experimental results revealed immature NPCs accumulated at the border of the high-grade tumor as well as in metastatic lesions of the brain. In mice, the researchers transplanted murine glioma cells embedded in a cell-impermeable, hollow fiber capsule into the brain. The study results showed that diffusible factors are secreted from the malignant cells to induce a neurogenic response. Vascular endolthelial growth (VEGfF) secreted by glioma cell also increased migration and proliferation of both adult human brain-derived neural stem and progenitor cells. Blocking VEGF signaling with inhibitory antibodies reduced NPC migration towards tumors. The authors concluded from their study results that their "data reveal a mechanism by which NPCs are attracted to CNS tumors and suggest that NPCs accumulate in human high-grade astrocytomas."
October 24: Cell Cycle State Detemines Cell Fate Propensity
In the September 26th issue of Cell, S. Paukin and L. Vallier from the University of Cambridge reported their study results on the underlying by which cell fate decisions are dependent upon the cell cycle. The investigators utilized a FUCCI reporter system in human pluripotent stem cells (hPSCs) in order to determine differentiation potential during progression of their cell cycle. The experimental results revealed that as the hPSCs enter early G1, Smad2/3 pathway is activated and in the nucleus Smad2/3 binds to p300 and TF (TGF-b transcription factor) resulting in hPSCs commitment to the endodermal lineage. In late G1 and G1/S of the cell cycle), cyclin D-CDK4/6 binds to Smad 2/3 which commits the hPSCs to the neuroectoderm lineage. With small molecules, the researchers were abel to direct differentiation of hPSCs to a specific tissue lineage. The authors concluded from their study that "cell fate decisions are tightly associated with the cell-cycle machinery and reveal insights in the mechanisms synchronizing differentiation and proliferation in developing tissues."
In the October 7th online early publication of Stem Cells, Q. Yan et al. from the University of Texas School of Medicine at Houston, published their study results on developing a single non-viral targeting vector on generating induce pluripotent stem cells (iPSCs). The investigators used a combination of Tet-On inducible gene expression system, Cre/loxP switching gene expression system, and alveolar epithelial type II cell (ATIIC)-specific Neomycin transgene expression system to reprogram somatic cells and subsequent lung alveolar epithelial cells. With the above different expression systems, a single copy of all the transgene could be knocked into a" specific site downstream of beta-2-microglobulin (B2M) gene locus at a high frequency without causing (B2M) dysfunction" in the iPSCs. Additionally, this novel reprogramming system allows for the exogenous reprogramming factors to be removed by transient expression of Cre recombinase. The experimental data also revealed that the resultant hiPSCs can be differentiated into a homogenous population of ATIICs with this novel reprogramming system. In mice treated with bleomycin, hiPSCs transplanted in the lungs were able to re-epithelial injured alveoli, restore pulmonary function, prevent lung fibrosis, and increase survival rates without tumorigenic side effects.