Inhibition of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells
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 ste...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2006-08, Vol.103 (31), p.11707-11712 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Chute, John P. Muramoto, Garrett G. Whitesides, John Colvin, Michael Safi, Rachid Chao, Nelson J. McDonnell, Donald P. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.0603806103 |
| format | Article |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0603806103</identifier><identifier>PMID: 16857736</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Aldehyde Dehydrogenase - antagonists & inhibitors ; Aldehyde Dehydrogenase - metabolism ; Aldehydes ; Animals ; Antigens, CD - metabolism ; B lymphocytes ; Biological Sciences ; Cell Differentiation - physiology ; Cells, Cultured ; Cellular biology ; Cellular differentiation ; Cultured cells ; Cytokines ; Hematopoietic stem cells ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - physiology ; Homeodomain Proteins - metabolism ; Humans ; Hydrogenases ; Isoenzymes - antagonists & inhibitors ; Isoenzymes - metabolism ; Mice ; Mice, SCID ; Myeloid cells ; p-Aminoazobenzene - analogs & derivatives ; Progenitor cells ; Retinal Dehydrogenase ; Retinoids ; Retinoids - metabolism ; Signal Transduction - physiology ; Stem cell transplantation ; Stem cells ; Transcription Factors - metabolism ; Vitamin A</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2006-08, Vol.103 (31), p.11707-11712</ispartof><rights>Copyright 2006 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 1, 2006</rights><rights>2006 by The National Academy of Sciences of the USA 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-ba392db636b539134e672a9156b24a313ddc82a95176d5c5129896714ee68dc43</citedby><cites>FETCH-LOGICAL-c596t-ba392db636b539134e672a9156b24a313ddc82a95176d5c5129896714ee68dc43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/103/31.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/30051596$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/30051596$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,725,778,782,801,883,27907,27908,53774,53776,58000,58233</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16857736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chute, John P.</creatorcontrib><creatorcontrib>Muramoto, Garrett G.</creatorcontrib><creatorcontrib>Whitesides, John</creatorcontrib><creatorcontrib>Colvin, Michael</creatorcontrib><creatorcontrib>Safi, Rachid</creatorcontrib><creatorcontrib>Chao, Nelson J.</creatorcontrib><creatorcontrib>McDonnell, Donald P.</creatorcontrib><title>Inhibition of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Aldehyde Dehydrogenase - antagonists & inhibitors</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehydes</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>B lymphocytes</subject><subject>Biological Sciences</subject><subject>Cell Differentiation - physiology</subject><subject>Cells, Cultured</subject><subject>Cellular biology</subject><subject>Cellular differentiation</subject><subject>Cultured cells</subject><subject>Cytokines</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - physiology</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Hydrogenases</subject><subject>Isoenzymes - antagonists & inhibitors</subject><subject>Isoenzymes - metabolism</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Myeloid cells</subject><subject>p-Aminoazobenzene - analogs & derivatives</subject><subject>Progenitor cells</subject><subject>Retinal Dehydrogenase</subject><subject>Retinoids</subject><subject>Retinoids - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Transcription Factors - metabolism</subject><subject>Vitamin A</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9v0zAUxy0EYl3hzAlkcZjEIZsd_4h9mTSVQStNQmJwtpzYbV0ldogdtP33OGq0ApednmR_3sfv-QvAO4wuMarIVe91vEQcEYE4RuQFWGAkccGpRC_BAqGyKgQt6Rk4j_GAEJJMoNfgDHPBqorwBYgbv3e1Sy54GLbwpjV2_2gs_DyVIexsfsBC7Q38bpPzwRl473Zet87v4MabsbERpr2Ftw-99nHWrMdOe7i2nU6hDy53NvA-2Q6ubNvGN-DVVrfRvp3rEvz8cvtjtS7uvn3drG7uioZJnopaE1mamhNeMyIxoZZXpZaY8bqkmmBiTCPyAcMVN6xhuJRC8gpTa7kwDSVLcH309mPdWdNYnwbdqn5wnR4eVdBO_Xvj3V7twm-FGaUlmQQXs2AIv0Ybk-pcbPIK2tswRsUFl6Jk5FkQSykrSmUGP_4HHsI45O-MqkSYIsGQyNDVEWqGEONgt08jY6Sm2NUUuzrFnjs-_L3piZ9zzgCcganzpCOKYIVxlaVL8OkZRG3Htk32IWX2_ZE9xBSGJ5ggxHDOjvwBkV3LjQ</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>Chute, John P.</creator><creator>Muramoto, Garrett G.</creator><creator>Whitesides, John</creator><creator>Colvin, Michael</creator><creator>Safi, Rachid</creator><creator>Chao, Nelson J.</creator><creator>McDonnell, Donald P.</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060801</creationdate><title>Inhibition of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells</title><author>Chute, John P. ; 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>16857736</pmid><doi>10.1073/pnas.0603806103</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aldehyde Dehydrogenase - antagonists & inhibitors Aldehyde Dehydrogenase - metabolism Aldehydes Animals Antigens, CD - metabolism B lymphocytes Biological Sciences Cell Differentiation - physiology Cells, Cultured Cellular biology Cellular differentiation Cultured cells Cytokines Hematopoietic stem cells Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - physiology Homeodomain Proteins - metabolism Humans Hydrogenases Isoenzymes - antagonists & inhibitors Isoenzymes - metabolism Mice Mice, SCID Myeloid cells p-Aminoazobenzene - analogs & derivatives Progenitor cells Retinal Dehydrogenase Retinoids Retinoids - metabolism Signal Transduction - physiology Stem cell transplantation Stem cells Transcription Factors - metabolism Vitamin A |
| title | Inhibition of Aldehyde Dehydrogenase and Retinoid Signaling Induces the Expansion of Human Hematopoietic Stem Cells |
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