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Recent studies have underscored the critical role of retinoic acid (RA) in the development of lineage-committed CD4 and CD8 T cells in vivo. We have shown that under acute graft-versus-host disease (GVHD) inflammatory conditions, RA is upregulated in the intestine and is proinflammatory, as GVHD lethality was attenuated when donor allogeneic T cells selectively expressed a dominant negative RA receptor α that blunted RA signaling. RA can function in an autocrine and paracrine fashion, and as such, the host cell lineage responsible for the production of RA metabolism and the specific RA-metabolizing enzymes that potentiate GVHD severity are unknown. In this study, we demonstrate that enhancing RA degradation in the host and to a lesser extent donor hematopoietic cells by overexpressing the RA-catabolizing enzyme CYP26A1 reduced GVHD. RA production is facilitated by retinaldehyde isoform-2 (RALDH2) preferentially expressed in dendritic cells (DCs). Conditionally deleted RA-synthesizing enzyme RALDH2 in host or to a lesser extent donor DCs reduced GVHD lethality. Improved survival in recipients with RALDH2-deleted DCs was associated with increased T cell death, impaired T effector function, increased regulatory T cell frequency, and augmented coinhibitory molecule expression on donor CD4+ T cells. In contrast, retinaldehydrogenase isoform-1 (RALDH1) is dominantly expressed in intestinal epithelial cells. Unexpectedly, conditional host intestinal epithelial cells RALDH1 deletion failed to reduce GVHD. These data demonstrate the critical role of both donor and especially host RALDH2+ DCs in driving murine GVHD and suggest RALDH2 inhibition or CYP26A1 induction as novel therapeutic strategies to prevent GVHD.

TBRT and ATRP are orthogonal initiation chemistries used in vinyl polymerisations. Here, we present the first combination of these techniques to readily create high molecular weight branched polyester macroinitiators capable of forming star copolymers from a range of methacrylate monomers. [ABSTRACT FROM AUTHOR]

Time-restricted feeding (RF) is known to shift the phasing of gene expression in most primary metabolic tissues, whereas a time misalignment between the suprachiasmatic nucleus circadian clock (SCNCC) and its peripheral CCs (PCC's) is known to induce various pathophysiological conditions, including a metabolic syndrome. We now report that a unique "light therapy," involving different light intensities (TZT0-ZT12150-TZT0-ZT12700 lx, TZT0-ZT1275-TZT0-ZT12150 lx, and TZT0-ZT12350-TZT0-ZT12700 lx), realigns the RF-generated misalignment between the SCNCC and the PCC's. Using such high-light regime, we show that through shifting the SCNCC and its activity, it is possible in a RF and "night-shifted mouse model" to prevent/correct pathophysiologies (e.g., a metabolic syndrome, a loss of memory, cardiovascular abnormalities). Our data indicate that such a "high-light regime" could be used as a unique chronotherapy, for those working on night shifts or suffering from jet-lag, in order to realign their SCNCC and PCC's, thereby preventing the generation of pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Although regeneration through the reprogramming of one cell lineage to another occurs in fish and amphibians, it has not been observed in mammals. We discovered in the mouse that during wound healing, adipocytes regenerate from myofibroblasts, a cell type thought to be differentiated and nonadipogenic. Myofibroblast reprogramming required neogenic hair follicles, which triggered bone morphogenetic protein (BMP) signaling and then activation of adipocyte transcription factors expressed during development. Overexpression of the BMP antagonist Noggin in hair follicles or deletion of the BMP receptor in myofibroblasts prevented adipocyte formation. Adipocytes formed from human keloid fibroblasts either when treated with BMP or when placed with human hair follicles in vitro. Thus, we identify the myofibroblast as a plastic cell type that may be manipulated to treat scars in humans.

Progressive tissue fibrosis is a major cause of the morbidity and mortality associated with repeated epithelial injuries and accumulation of myofibroblasts. Successful treatment options are limited by an incomplete understanding of the molecular mechanisms that regulate myofibroblast accumulation. Here, we employed in vivo lineage tracing and real-time gene expression transgenic reporting methods to analyze the early embryonic transcription factor T-box gene 4 (TBX4), and determined that TBX4-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult lung. In a murine model, ablation of TBX4-expressing cells or disruption of TBX4 signaling attenuated lung fibrosis after bleomycin-induced injury. Furthermore, TBX4 regulated hyaluronan synthase 2 production to enable fibroblast invasion of matrix both in murine models and in fibroblasts from patients with severe pulmonary fibrosis. These data identify TBX4 as a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis. Targeting TBX4 and downstream factors that regulate fibroblast invasiveness could lead to therapeutic approaches in lung fibrosis.

The identification of cell types of origin for cancer has important implications for tumor stratification and personalized treatment. For prostate cancer, the cell of origin has been intensively studied, but it has remained unclear whether basal or luminal epithelial cells, or both, represent cells of origin under physiological conditions in vivo. Here, we use a novel lineage-tracing strategy to assess the cell of origin in a diverse range of mouse models, including Nkx3.1(+/-); Pten(+/-), Pten(+/-), Hi-Myc, and TRAMP mice, as well as a hormonal carcinogenesis model. Our results show that luminal cells are consistently the observed cell of origin for each model in situ; however, explanted basal cells from these mice can generate tumors in grafts. Consequently, we propose that luminal cells are favored as cells of origin in many contexts, whereas basal cells only give rise to tumors after differentiation into luminal cells.

Dominant mutations in cardiac transcription factor genes cause human inherited congenital heart defects (CHDs); however, their molecular basis is not understood. Interactions between transcription factors and the Brg1/Brm-associated factor (BAF) chromatin remodelling complex suggest potential mechanisms; however, the role of BAF complexes in cardiogenesis is not known. In this study, we show that dosage of Brg1 is critical for mouse and zebrafish cardiogenesis. Disrupting the balance between Brg1 and disease-causing cardiac transcription factors, including Tbx5, Tbx20 and Nkx2-5, causes severe cardiac anomalies, revealing an essential allelic balance between Brg1 and these cardiac transcription factor genes. This suggests that the relative levels of transcription factors and BAF complexes are important for heart development, which is supported by reduced occupancy of Brg1 at cardiac gene promoters in Tbx5 haploinsufficient hearts. Our results reveal complex dosage-sensitive interdependence between transcription factors and BAF complexes, providing a potential mechanism underlying transcription factor haploinsufficiency, with implications for multigenic inheritance of CHDs.

Circulating, soluble polymer–drug conjugates have been utilised for many years to aid the delivery of sensitive, poorly-soluble or cytotoxic drugs, prolong circulation times or minimise side effects. Long-acting therapeutics are increasing in their healthcare importance, with intramuscular and subcutaneous administration of liquid formulations being most common. Degradable implants also offer opportunities and the use of polymer–prodrug conjugates as implant materials has not been widely reported in this context. Here, the potential for polymer–prodrug conjugates of the water soluble nucleoside reverse transciption inhibitor emtricitabine (FTC) is studied. A novel diol monomer scaffold, allowing variation of prodrug substitution, has been used to form polyesters and polycarbonates by step-growth polymerisation. Materials have been screened for physical properties that enable implant formation, studied for drug release to provide mechanistic insights, and tunable prolonged release of FTC has been demonstrated over a period of at least two weeks under relevant physiological conditions. [ABSTRACT FROM AUTHOR]