Article

Chute, J.P. et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc. Natl. Acad. Sci. USA 103, 11707-11712

Duke University, Durham, North Carolina, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2006; 103(31):11707-12. DOI: 10.1073/pnas.0603806103
Source: PubMed

ABSTRACT

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 diabetic/severe 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.

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Available from: Rachid Safi, Aug 13, 2014
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    • "The functional role of ALDH has been studied, with specific inhibitor of ALDH, diethylaminobenzaldehyde (DEAB), which was able to alter the molecular and cellular mechanisms that control self-renewal capacity of human HSC (Chute et al., 2006). The evidence of ALDH involvement in the physiology of HSC was further highlighted by a series of studies devoted to purification/analysis of highly immature progenitor cells, particularly in human cord blood (CB) as well as in murine bone marrow (BM) (Christ et al., 2007; Juopperi et al., 2007; Hess et al., 2006). "

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    • "Paraffin blocks from 47 individual patients, four fresh specimens of malignant PT and their xenografted tumors, were examined by immunohistochemical staining for the following markers: CD44 (HCAM), CD29 (integrin β-1), CD106 (VCAM-1), CD166 (ALCAM), CD105 (Endoglin), CD90 (Thy-1) [17-20], GD2 (ganglioside) [11], CD117(c-kit receptor) [21], ALDH1 [15], embryonic stem cell marker Oct-4 (Octamer-4 in abbreviation), CD34 [22], CD10, p53, p63, Ki-67, Bcl-2 [23] and vimentin [24]. Mesenchymal progenitor cell-line HS-5 was chosen as a control. "
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    • "The aldehyde dehydrogenase family, of which ALDH1 is a member, is a family of cytosolic isoenzymes, which are highly expressed in many stem and progenitor cells [40]. Its known functions include the conversion of retinol to retinoic acids and the oxidation of toxic aldehyde metabolites, like those formed during alcohol metabolism and with certain chemotherapeutics such as cyclophosphamide and cisplatin [41, 42]. As with CD44, the lead for investigating ALDH as a marker for CSCs in HNSCC followed identification in other solid malignancies such as breast, colon, liver, and lung tumors [43–46]. "
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