Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis
A critical issue for clinical utilization of human ES cells (hESCs) is whether they can generate terminally mature progenies with normal function. We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cell...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2008-09, Vol.105 (35), p.13087-13092 |
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| creator | Ma, Feng Ebihara, Yasuhiro Umeda, Katsutsugu Sakai, Hiromi Hanada, Sachiyo Zhang, Hong Zaike, Yuji Tsuchida, Eishun Nakahata, Tatsutoshi Nakauchi, Hiromitsu Tsuji, Kohichiro |
| description | A critical issue for clinical utilization of human ES cells (hESCs) is whether they can generate terminally mature progenies with normal function. We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cells. Large numbers of hESCs-derived erythroid progenitors generated by the coculture enabled us to analyze the development of erythropoiesis at a clone level and investigate their function. The results showed that the globin expression in the erythroid cells in individual clones changed in a time-dependent manner. In particular, embryonic ε-globin-expressing erythroid cells from individual clones decreased, whereas adult-type β-globin-expressing cells increased to [almost equal to]100% in all clones we examined, indicating that the cells undergo definitive hematopoiesis. Enucleated erythrocytes also appeared among the clonal progeny. A comparison analysis showed that hESC-derived erythroid cells took a similar differentiation pathway to human cord blood CD34⁺ progenitor-derived cells when examined for the expression of glycophorin A, CD71 and CD81. Furthermore, these hESC-derived erythroid cells could function as oxygen carriers and had a sufficient glucose-6-phosphate dehydrogenase activity. The present study should provide an experimental model for exploring early development of human erythropoiesis and hemoglobin switching and may help in the discovery of drugs for hereditary diseases in erythrocyte development. |
| doi_str_mv | 10.1073/pnas.0802220105 |
| format | Article |
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We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cells. Large numbers of hESCs-derived erythroid progenitors generated by the coculture enabled us to analyze the development of erythropoiesis at a clone level and investigate their function. The results showed that the globin expression in the erythroid cells in individual clones changed in a time-dependent manner. In particular, embryonic ε-globin-expressing erythroid cells from individual clones decreased, whereas adult-type β-globin-expressing cells increased to [almost equal to]100% in all clones we examined, indicating that the cells undergo definitive hematopoiesis. Enucleated erythrocytes also appeared among the clonal progeny. A comparison analysis showed that hESC-derived erythroid cells took a similar differentiation pathway to human cord blood CD34⁺ progenitor-derived cells when examined for the expression of glycophorin A, CD71 and CD81. Furthermore, these hESC-derived erythroid cells could function as oxygen carriers and had a sufficient glucose-6-phosphate dehydrogenase activity. The present study should provide an experimental model for exploring early development of human erythropoiesis and hemoglobin switching and may help in the discovery of drugs for hereditary diseases in erythrocyte development.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0802220105</identifier><identifier>PMID: 18755895</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animal models ; Animals ; Antigens, CD - metabolism ; Biological Sciences ; CD34 antigen ; CD81 antigen ; Cell culture ; Cell Differentiation ; Cell Line ; Clone Cells ; Cloning ; Coculture Techniques ; Comparative analysis ; Cord blood ; Cultured cells ; Differentiation ; Drug development ; Drug discovery ; Embryonic stem cells ; Embryonic Stem Cells - cytology ; Embryos ; Erythrocytes ; Erythrocytes - cytology ; Erythrocytes - metabolism ; Erythroid cells ; Erythroid progenitor cells ; Erythropoiesis ; Fetuses ; Flow Cytometry ; Gene expression ; Gene Expression Regulation, Developmental ; Globins - genetics ; Globins - metabolism ; Glucose ; Glucosephosphate dehydrogenase ; Glycophorin - metabolism ; Hematopoiesis ; Hematopoiesis - genetics ; Hematopoietic stem cells ; Hemoglobin ; Hemopoiesis ; Hereditary diseases ; Humans ; Liver - cytology ; Liver - embryology ; Mice ; Oxygen ; Progenitor cells ; Progeny ; Receptors, Transferrin - metabolism ; Stem cells ; Stromal cells ; Stromal Cells - cytology ; Tetraspanin 28 ; Time Factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (35), p.13087-13092</ispartof><rights>Copyright 2008 The National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Sep 2, 2008</rights><rights>2008 by The National Academy of Sciences of the USA 2008</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c620t-6ac804381bb7f40e3569bbd07500a00f844ee0b0cfe05b88972a2134d80bb6503</citedby><cites>FETCH-LOGICAL-c620t-6ac804381bb7f40e3569bbd07500a00f844ee0b0cfe05b88972a2134d80bb6503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/105/35.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25463995$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25463995$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18755895$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ma, Feng</creatorcontrib><creatorcontrib>Ebihara, Yasuhiro</creatorcontrib><creatorcontrib>Umeda, Katsutsugu</creatorcontrib><creatorcontrib>Sakai, Hiromi</creatorcontrib><creatorcontrib>Hanada, Sachiyo</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Zaike, Yuji</creatorcontrib><creatorcontrib>Tsuchida, Eishun</creatorcontrib><creatorcontrib>Nakahata, Tatsutoshi</creatorcontrib><creatorcontrib>Nakauchi, Hiromitsu</creatorcontrib><creatorcontrib>Tsuji, Kohichiro</creatorcontrib><title>Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>A critical issue for clinical utilization of human ES cells (hESCs) is whether they can generate terminally mature progenies with normal function. We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cells. Large numbers of hESCs-derived erythroid progenitors generated by the coculture enabled us to analyze the development of erythropoiesis at a clone level and investigate their function. The results showed that the globin expression in the erythroid cells in individual clones changed in a time-dependent manner. In particular, embryonic ε-globin-expressing erythroid cells from individual clones decreased, whereas adult-type β-globin-expressing cells increased to [almost equal to]100% in all clones we examined, indicating that the cells undergo definitive hematopoiesis. Enucleated erythrocytes also appeared among the clonal progeny. A comparison analysis showed that hESC-derived erythroid cells took a similar differentiation pathway to human cord blood CD34⁺ progenitor-derived cells when examined for the expression of glycophorin A, CD71 and CD81. Furthermore, these hESC-derived erythroid cells could function as oxygen carriers and had a sufficient glucose-6-phosphate dehydrogenase activity. The present study should provide an experimental model for exploring early development of human erythropoiesis and hemoglobin switching and may help in the discovery of drugs for hereditary diseases in erythrocyte development.</description><subject>Animal models</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>Biological Sciences</subject><subject>CD34 antigen</subject><subject>CD81 antigen</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Clone Cells</subject><subject>Cloning</subject><subject>Coculture Techniques</subject><subject>Comparative analysis</subject><subject>Cord blood</subject><subject>Cultured cells</subject><subject>Differentiation</subject><subject>Drug development</subject><subject>Drug discovery</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Embryos</subject><subject>Erythrocytes</subject><subject>Erythrocytes - cytology</subject><subject>Erythrocytes - metabolism</subject><subject>Erythroid cells</subject><subject>Erythroid progenitor cells</subject><subject>Erythropoiesis</subject><subject>Fetuses</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Globins - genetics</subject><subject>Globins - metabolism</subject><subject>Glucose</subject><subject>Glucosephosphate dehydrogenase</subject><subject>Glycophorin - metabolism</subject><subject>Hematopoiesis</subject><subject>Hematopoiesis - genetics</subject><subject>Hematopoietic stem cells</subject><subject>Hemoglobin</subject><subject>Hemopoiesis</subject><subject>Hereditary diseases</subject><subject>Humans</subject><subject>Liver - cytology</subject><subject>Liver - embryology</subject><subject>Mice</subject><subject>Oxygen</subject><subject>Progenitor cells</subject><subject>Progeny</subject><subject>Receptors, Transferrin - metabolism</subject><subject>Stem cells</subject><subject>Stromal cells</subject><subject>Stromal Cells - cytology</subject><subject>Tetraspanin 28</subject><subject>Time Factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1v1DAQxSMEotvCmRNg9YDEIe34M84FCVVQkCpxgJ4tJxl3vUrixXYq9r8nYVdd4NLTjDS_eePnVxSvKFxQqPjldrTpAjQwxoCCfFKsKNS0VKKGp8UKgFWlFkycFKcpbQCglhqeFydUV1LqWq4KvMYRo80-jCQ44qaxXXrbE4y7vI6h3WVMxMUwkPU02JHg0MRdGH1LUsaBtNj3ZYfR32NHOnR-9HnuyRoHm8M2eEw-vSieOdsnfHmoZ8Xt508_rr6UN9-uv159vClbxSCXyrYaBNe0aSonALlUddN0UEkAC-C0EIjQQOsQZKN1XTHLKBedhqZREvhZ8WGvu52aAbsWxxxtb7bRDzbuTLDe_DsZ_drchXvDJFNSslng3UEghp8TpmwGnxaLdsQwJaNqCVVV0UdBBowrrtQMnv8HbsIU5w9eGMprQfWidrmH2hhSiugenkzBLEGbJWhzDHreePO30yN_SHYG3h-AZfMoJw2XhnLQlXFT32f8lWeWPMLOyOs9skk5xAeGSaF4_efc2_3c2WDsXfTJ3H5fDAKVXAou-G96-NGU</recordid><startdate>20080902</startdate><enddate>20080902</enddate><creator>Ma, Feng</creator><creator>Ebihara, Yasuhiro</creator><creator>Umeda, Katsutsugu</creator><creator>Sakai, Hiromi</creator><creator>Hanada, Sachiyo</creator><creator>Zhang, Hong</creator><creator>Zaike, Yuji</creator><creator>Tsuchida, Eishun</creator><creator>Nakahata, Tatsutoshi</creator><creator>Nakauchi, Hiromitsu</creator><creator>Tsuji, Kohichiro</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080902</creationdate><title>Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis</title><author>Ma, Feng ; Ebihara, Yasuhiro ; Umeda, Katsutsugu ; Sakai, Hiromi ; Hanada, Sachiyo ; Zhang, Hong ; Zaike, Yuji ; Tsuchida, Eishun ; Nakahata, Tatsutoshi ; Nakauchi, Hiromitsu ; Tsuji, Kohichiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c620t-6ac804381bb7f40e3569bbd07500a00f844ee0b0cfe05b88972a2134d80bb6503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Antigens, CD - 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metabolism</topic><topic>Hematopoiesis</topic><topic>Hematopoiesis - genetics</topic><topic>Hematopoietic stem cells</topic><topic>Hemoglobin</topic><topic>Hemopoiesis</topic><topic>Hereditary diseases</topic><topic>Humans</topic><topic>Liver - cytology</topic><topic>Liver - embryology</topic><topic>Mice</topic><topic>Oxygen</topic><topic>Progenitor cells</topic><topic>Progeny</topic><topic>Receptors, Transferrin - metabolism</topic><topic>Stem cells</topic><topic>Stromal cells</topic><topic>Stromal Cells - cytology</topic><topic>Tetraspanin 28</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ma, Feng</creatorcontrib><creatorcontrib>Ebihara, Yasuhiro</creatorcontrib><creatorcontrib>Umeda, Katsutsugu</creatorcontrib><creatorcontrib>Sakai, Hiromi</creatorcontrib><creatorcontrib>Hanada, Sachiyo</creatorcontrib><creatorcontrib>Zhang, Hong</creatorcontrib><creatorcontrib>Zaike, Yuji</creatorcontrib><creatorcontrib>Tsuchida, Eishun</creatorcontrib><creatorcontrib>Nakahata, Tatsutoshi</creatorcontrib><creatorcontrib>Nakauchi, Hiromitsu</creatorcontrib><creatorcontrib>Tsuji, Kohichiro</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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We recently developed a method for efficient production of hematopoietic progenitors from hESCs by coculture with murine fetal liver-derived stromal cells. Large numbers of hESCs-derived erythroid progenitors generated by the coculture enabled us to analyze the development of erythropoiesis at a clone level and investigate their function. The results showed that the globin expression in the erythroid cells in individual clones changed in a time-dependent manner. In particular, embryonic ε-globin-expressing erythroid cells from individual clones decreased, whereas adult-type β-globin-expressing cells increased to [almost equal to]100% in all clones we examined, indicating that the cells undergo definitive hematopoiesis. Enucleated erythrocytes also appeared among the clonal progeny. A comparison analysis showed that hESC-derived erythroid cells took a similar differentiation pathway to human cord blood CD34⁺ progenitor-derived cells when examined for the expression of glycophorin A, CD71 and CD81. Furthermore, these hESC-derived erythroid cells could function as oxygen carriers and had a sufficient glucose-6-phosphate dehydrogenase activity. The present study should provide an experimental model for exploring early development of human erythropoiesis and hemoglobin switching and may help in the discovery of drugs for hereditary diseases in erythrocyte development.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>18755895</pmid><doi>10.1073/pnas.0802220105</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2008-09, Vol.105 (35), p.13087-13092 |
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| subjects | Animal models Animals Antigens, CD - metabolism Biological Sciences CD34 antigen CD81 antigen Cell culture Cell Differentiation Cell Line Clone Cells Cloning Coculture Techniques Comparative analysis Cord blood Cultured cells Differentiation Drug development Drug discovery Embryonic stem cells Embryonic Stem Cells - cytology Embryos Erythrocytes Erythrocytes - cytology Erythrocytes - metabolism Erythroid cells Erythroid progenitor cells Erythropoiesis Fetuses Flow Cytometry Gene expression Gene Expression Regulation, Developmental Globins - genetics Globins - metabolism Glucose Glucosephosphate dehydrogenase Glycophorin - metabolism Hematopoiesis Hematopoiesis - genetics Hematopoietic stem cells Hemoglobin Hemopoiesis Hereditary diseases Humans Liver - cytology Liver - embryology Mice Oxygen Progenitor cells Progeny Receptors, Transferrin - metabolism Stem cells Stromal cells Stromal Cells - cytology Tetraspanin 28 Time Factors |
| title | Generation of functional erythrocytes from human embryonic stem cell-derived definitive hematopoiesis |
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