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...

During the initial assembly of the olfactory pathway, the behavior of olfactory axons changes as they grow from the olfactory epithelium toward the telencephalic vesicle. The axons exit the epithelium singly or in small fascicles, and their growth cones are simple and bullet-shaped. Outside the epithelium, they make a sharp dorsal turn and fasciculate into a single nerve; the growth cones remain simple. Upon entering the ventromedial telencephalon, the axons defasciculate, branch extensively, and end in complex, lamellate growth cones which extend toward the ventrolateral aspect of the telencephalic vesicle. The distribution of laminin, collagen-IV, and fibronectin varies in register with these changes in olfactory axon and growth cone behavior. Each of these extracellular matrix molecules influences olfactory neurite outgrowth and growth cone morphology in vitro consistent with its distribution in vivo. The distribution of E-cadherin, L1, neural cell adhesion molecule (NCAM) and the polysialated form of NCAM also varies in register with changes in olfactory axon behavior. In vitro, L1 modulates embryonic olfactory neurite outgrowth and growth cone morphology consistent with its distribution in vivo. Thus, olfactory axon trajectory, fasciculation, and growth cone morphology change within distinct adhesive environments in the nascent olfactory pathway, and some of the molecules that characterize these environments have differential effects upon olfactory neurite growth and growth cone morphology. Consequently, the patterned expression and activity of extracellular matrix and cell surface adhesion molecules may contribute to the initial assembly of the olfactory pathway.

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