Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic͞severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34 ؉ CD38 ؊ lin ؊ cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.retinoic acid ͉ self-renewal ͉ diethylaminobenzaldehyde ͉ long-term repopulating cells H ematopoietic stem cells (HSCs) possess the unique capacity to self-renew and give rise to all mature lymphohematopoietic progeny throughout the lifetime of an individual (1, 2). Several molecular pathways that regulate HSC self-renewal have now been identified, including Notch (3), HOXB4 (4), Wnt (5), and bone morphogenetic protein signaling pathways (6). The osteoblastic niche for HSCs within the bone marrow (BM) has also been characterized (7,8). Despite these advances in understanding HSC biology, clinical methods to amplify human HSCs have yet to be realized, and characterization of the pathways that regulate HSC self-renewal continues to evolve.Two decades ago, Colvin et al. (9,10) demonstrated that the intracellular enzyme, aldehyde dehydrogenase (ALDH), protected BM progenitors from the cytotoxic effects of cyclophosphamide by deactivation of its metabolite, 4-hydroxycyclophosphamide (9, 10). Several isoforms of ALDH have been identified, with ALDH1 being the primary isoform expressed within human hematopoietic progenitors (11,12). Recent studies have shown that human and murine hematopoietic progenitors can be isolated by using a fluorescently labeled dye specific for ALDH activity (13-16) and cord blood (CB) ALDH br lin Ϫ cells are enriched for nonobese diabetic͞severe combined immunodeficiency (NOD͞SCID) mouse repopulating cells [SCID-repopulating cells (SRCs)] (15, 16). Although these data demonstrate that ALDH is a selectable marker for human stem͞progenitor cells, the HSC-specific function of ALDH remains unknown. In the liver, ALDH1 contributes prima...
We have characterized the adaptations of Helicobacter pylori to a rarely captured event in the evolution of its impact on host biology-the transition from chronic atrophic gastritis (ChAG) to gastric adenocarcinoma-and defined the impact of these adaptations on an intriguing but poorly characterized interaction between this bacterium and gastric epithelial stem cells. Bacterial isolates were obtained from a single human host colonized with a single dominant strain before and after his progression from ChAG to gastric adenocarcinoma during a 4-year interval. Draft genome assemblies were generated from two isolates, one ChAG-associated, the other cancer-associated. The cancer-associated strain was less fit in a gnotobiotic transgenic mouse model of human ChAG and better able to establish itself within a mouse gastric epithelial progenitorderived cell line (mGEP) that supports bacterial attachment. GeneChip-based comparisons of the transcriptomes of mGEPs and a control mouse gastric epithelial cell line revealed that, upon infection, the cancer-associated strain regulates expression of GEP-associated signaling and metabolic pathways, and tumor suppressor genes associated with development of gastric cancer in humans, in a manner distinct from the ChAG-associated isolate. The effects on GEP metabolic pathways, some of which were confirmed in gnotobiotic mice, together with observed changes in the bacterial transcriptome are predicted to support aspects of an endosymbiosis between this microbe and gastric stem cells. These results provide insights about how H. pylori may adapt to and influence stem cell biology and how its intracellular residency could contribute to gastric tumorigenesis. microbial pathogenesis ͉ intracellular bacteria ͉ genome sequencing ͉ functional genomics ͉ gnotobiotic mice
The human nuclear receptor liver receptor homolog 1 (hLRH-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor SHP and has been thought to be ligand-independent. We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs. Electron density indicates phospholipid bound within the ligand-binding pocket, which we confirm using mass spectrometry of solvent-extracted samples. We further show that pocket mutations reduce phospholipid binding and receptor activity in vivo. Our results indicate that hLRH-1's control of gene expression is mediated by phospholipid binding, and establish hLRH-1 as a novel target for compounds designed to slow breast cancer development.
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