SummaryHepatocytes and cholangiocytes self renew following liver injury. Following severe injury hepatocytes are increasingly senescent, whether Hepatic Progenitor Cells (HPCs) then contribute to liver regeneration is unclear. Here, we describe a mouse model where Mdm2 is inducibly deleted in over 98% of hepatocytes, causing apoptosis, necrosis and senescence with nearly all hepatocytes expressing p21. This results in florid HPC activation, which is necessary for survival, followed by complete, functional liver reconstitution. HPCs isolated from genetically normal mice, using cell surface markers, were highly expandable and phenotypically stable in vitro. These HPCs were transplanted into adult mouse livers where hepatocyte Mdm2 was repeatedly deleted, creating a non-competitive repopulation assay. Transplanted HPCs contributed significantly to restoration of liver parenchyma, regenerating hepatocytes and biliary epithelia, highlighting their in vivo lineage potency. HPCs are therefore a potential future alternative to hepatocyte or liver transplantation for liver disease.

Abstract5-Hydroxymethylcytosine (hmC) is an oxidation product of 5-methylcytosine (mC) present in DNA of most mammalian cells. Reduction of hmC levels in DNA is a hallmark of cancers. Elucidating the dynamics of this oxidation reaction and the lifetime of hmC in DNA is fundamental to understanding hmC function. Using stable isotope labeling of cytosine derivatives in the DNA of mammalian cells and ultrasensitive tandem liquid-chromatography mass spectrometry (LCMS), we show that the majority of hmC is a stable modification, as opposed to a transient intermediate. In contrast with DNA methylation, which occurs immediately during replication, hmC forms slowly over the first 30 h following DNA synthesis. Isotopic labeling of DNA in mouse tissues confirmed the stability of hmC in vivo and demonstrated a relationship between global levels of hmC and cell proliferation. These insights have important implications for understanding the states of chemically modified DNA bases in health and disease.Methylation of cytosine (C) at C-5 to form 5-methylcytosine (mC), by DNA methyltransferase enzymes, is an important epigenetic DNA modification that is essential for development, normal function and disease in all mammals 1 . In 2009, it was robustly demonstrated that 5mC could be enzymatically oxidized to 5-hydroxymethylcytosine (hmC) 2,3 . The initial discoveries were made in genomic DNA isolated from mouse brain and embryonic stem (mES) cell DNA, but hmC has subsequently been detected in all mammalian tissues 4 . In contrast with global DNA methylation levels which are stable across tissues, the levels of hmC are highly tissue-specific, ranging between 0.03 % of all cytosines in the spleen and 0.7 % in the brain 4 , and are reduced up to 8-fold in cancer tissues relative

We demonstrate that the comparison of Tully-Fisher relations (TFRs) derived from global HI line widths to TFRs derived from the circular velocity profiles of dynamical models (or stellar kinematic observations corrected for asymmetric drift) is vulnerable to systematic and uncertain biases introduced by the different measures of rotation used. We therefore argue that to constrain the relative locations of the TFRs of spiral and S0 galaxies, the same tracer and measure must be used for both samples. Using detailed near-infrared imaging and the circular velocities of axisymmetric Jeans models of 14 nearby edge-on Sa-Sb spirals and 14 nearby edge-on S0s drawn from a range of environments, we find that S0s lie on a TFR with the same slope as the spirals, but are on average 0.53+/-0.15 mag fainter at Ks-band at a given rotational velocity. This is a significantly smaller offset than that measured in earlier studies of the S0 TFR, which we attribute to our elimination of the bias associated with using different rotation measures and our use of earlier type spirals as a reference. Since our measurement of the offset avoids systematic biases, it should be preferred to previous estimates. A spiral stellar population in which star formation is truncated would take ~1 Gyr to fade by 0.53 mag at Ks-band. If S0s are the products of a simple truncation of star formation in spirals, then this finding is difficult to reconcile with the observed evolution of the spiral/S0 fraction with redshift. Recent star formation could explain the observed lack of fading in S0s, but the offset of the S0 TFR persists as a function of both stellar and dynamical mass. We show that the offset of the S0 TFR could therefore be explained by a systematic difference between the total mass distributions of S0s and spirals, in the sense that S0s need to be smaller or more concentrated than spirals.Comment: Accepted for publication in MNRAS; 17 pages; v2 incorporates minor proof corrections and updated reference

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The cytoplasmic domains of integrin ␤ subunits are involved in bidirectional transmembrane signaling. We report that the cytoplasmic domain of the integrin ␤

Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury. We therefore examined a model without injury; a single i.v. injection of unfractionated BMCs in healthy mice. This induced ductular reactions (DRs) in healthy mice. We demonstrate that macrophages within the unfractionated BMCs are responsible for the production of DRs, engrafting in the recipient liver and localizing to the DRs. Engrafted macrophages produce the cytokine TWEAK (TNF-like weak inducer of apoptosis) in situ. We go on to show that recombinant TWEAK activates DRs and that BMC mediated DRs are TWEAK dependent. DRs are accompanied by liver growth, occur in the absence of liver tissue injury and hepatic progenitor cells can be isolated from the livers of mice with DRs. Overall these results reveal a hitherto undescribed mechanism linking macrophage infiltration to DRs in the liver and highlight a rationale for macrophage derived cell therapy in regenerative medicine.liver regeneration | adult stem cell

Abstract. The adhesive and signaling functions of integrins are regulated through their cytoplasmic domains. We identified a novel 111 residue polypeptide, designated 133-endonexin, that interacted with the cytoplasmic tail of the ~3 integrin subunit in a yeast two-hybrid system. This interaction is structurally specific, since it was reduced by 64% by a point mutation in the 133 cytoplasmic tail ($752----~P) that disrupts integrin signaling. Moreover, this interaction is integrin subunit specific since it was not observed with the cytoplasmic tails of the eqlb, {31, or 132 subunits. 133-Endonexin fusion proteins bound selectively to detergent-solubilized 133 from platelets and human umbilical vein endothelial cells, and 133-endonexin mRNA and protein were detected in platelets and other tissues. A related mRNA encoded a larger polypeptide that failed to bind to 13 integrin tails. The apparent specificity of 133-endonexin for the 133 integrin subunit suggests potential mechanisms for selective modulation of integrin functions.

Most Milky Way globular clusters (GCs) exhibit measurable flattening, even if on a very low level. Both cluster rotation and tidal fields are thought to cause this flattening. Nevertheless, rotation has only been confirmed in a handful of GCs, based mostly on individual radial velocities at large radii. We are conducting a survey of the central kinematics of Galactic GCs using the new Integral Field Unit instrument VIRUS-W. We detect rotation in all 11 GCs that we have observed so far, rendering it likely that a large majority of the Milky Way GCs rotate. We use published catalogs of the ACS survey of GCs to derive central ellipticities and position angles. We show that in all cases where the central ellipticity permits an accurate measurement of the position angle, those angles are in excellent agreement with the kinematic position angles that we derive from the VIRUS-W velocity fields. We find an unexpected tight correlation between central rotation and outer ellipticity, indicating that rotation drives flattening for the objects in our sample. We also find a tight correlation between central rotation and published values for the central velocity dispersion, most likely due to rotation impacting the old dispersion measurements. † This paper includes data taken at The McDonald Observatory of The University of Texas at Austin.