The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny
The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fe...
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| description | The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117(++)CD203c(+) mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38-CD34(++) and CD133(+)CD34(++) cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver. |
| doi_str_mv | 10.1371/journal.pone.0097312 |
| format | Article |
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Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117(++)CD203c(+) mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38-CD34(++) and CD133(+)CD34(++) cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0097312</identifier><identifier>PMID: 24819392</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Analysis ; Animals ; Biology and Life Sciences ; Biomedical research ; Blood Cells - cytology ; Bone marrow ; CD34 antigen ; CD38 antigen ; Cell Transplantation ; Colony-forming cells ; Cytokines ; Cytometry ; Erythrocytes ; Female ; Fetal development ; Fetus - cytology ; Fetus - embryology ; Fetuses ; Flow cytometry ; Hematopoiesis ; Hematopoietic stem cells ; Hematopoietic Stem Cells - cytology ; Hepatocytes ; Humans ; Hybrid Cells - cytology ; Immune response ; Immunodeficiency ; Laboratories ; Liver ; Liver - cytology ; Liver - embryology ; Liver transplantation ; Liver transplants ; Lymphocytes B ; Lymphocytes T ; Mast cells ; Mast Cells - cytology ; Medicine and Health Sciences ; Mice ; Mice, Transgenic ; Monocytes ; Morphogenesis ; Neonates ; Ontogeny ; Population ; Pregnancy ; Pregnant women ; Research and Analysis Methods ; Rodents ; Stem cell transplantation ; Stem cells ; Transplantation ; Transplants & implants ; U-Plasminogen activator ; Urokinase ; Urokinase-Type Plasminogen Activator - genetics</subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e97312-e97312</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Muench et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Muench et al 2014 Muench et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3197c22560755f07d8cdc5f085d02b2af9f77a58d7c3b19929f50d01f3c25e423</citedby><cites>FETCH-LOGICAL-c692t-3197c22560755f07d8cdc5f085d02b2af9f77a58d7c3b19929f50d01f3c25e423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018295/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018295/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24819392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bertolini, Francesco</contributor><creatorcontrib>Muench, Marcus O</creatorcontrib><creatorcontrib>Beyer, Ashley I</creatorcontrib><creatorcontrib>Fomin, Marina E</creatorcontrib><creatorcontrib>Thakker, Rahul</creatorcontrib><creatorcontrib>Mulvaney, Usha S</creatorcontrib><creatorcontrib>Nakamura, Masato</creatorcontrib><creatorcontrib>Suemizu, Hiroshi</creatorcontrib><creatorcontrib>Bárcena, Alicia</creatorcontrib><title>The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117(++)CD203c(+) mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38-CD34(++) and CD133(+)CD34(++) cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Muench, Marcus O</au><au>Beyer, Ashley I</au><au>Fomin, Marina E</au><au>Thakker, Rahul</au><au>Mulvaney, Usha S</au><au>Nakamura, Masato</au><au>Suemizu, Hiroshi</au><au>Bárcena, Alicia</au><au>Bertolini, Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-05-12</date><risdate>2014</risdate><volume>9</volume><issue>5</issue><spage>e97312</spage><epage>e97312</epage><pages>e97312-e97312</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The liver plays a vital role in hematopoiesis during mammalian prenatal development but its hematopoietic output declines during the perinatal period. Nonetheless, hepatic hematopoiesis is believed to persist into adulthood. We sought to model human adult-liver hematopoiesis by transplantation of fetal and neonatal hematopoietic stem cells (HSCs) into adult immunodeficient mice. Livers were found to be engrafted with human cells consisting primarily of monocytes and B-cells with lesser contributions by erythrocytes, T-cells, NK-cells and mast-cells. A resident population of CD117(++)CD203c(+) mast cells was also documented in human midgestation liver, indicating that these cells comprise part of the liver's resident immune cell repertoire throughout human ontogeny. The murine liver was shown to support human multilineage hematopoiesis up to 321 days after transplant. Evidence of murine hepatic hematopoiesis was also found in common mouse strains as old as 2 years. Human HSC engraftment of the murine liver was demonstrated by detection of high proliferative-potential colony-forming cells in clonal cultures, observation of CD38-CD34(++) and CD133(+)CD34(++) cells by flow cytometry, and hematopoietic reconstitution of secondary transplant recipients of chimeric liver cells. Additionally, chimeric mice with both hematopoietic and endothelial reconstitution were generated by intrasplenic injection of immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene. In conclusion, the murine liver is shown to be a hematopoietic organ throughout adult life that can also support human hematopoiesis in severely immunodeficient strains. Further humanization of the murine liver can be achieved in mice harboring an uPA transgene, which support engraftment of non-hematopoietic cells types. Thus, offering a model system to study the interaction of diverse human liver cell types that regulate hematopoiesis and immune function in the liver.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24819392</pmid><doi>10.1371/journal.pone.0097312</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e97312-e97312 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1523873879 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Analysis Animals Biology and Life Sciences Biomedical research Blood Cells - cytology Bone marrow CD34 antigen CD38 antigen Cell Transplantation Colony-forming cells Cytokines Cytometry Erythrocytes Female Fetal development Fetus - cytology Fetus - embryology Fetuses Flow cytometry Hematopoiesis Hematopoietic stem cells Hematopoietic Stem Cells - cytology Hepatocytes Humans Hybrid Cells - cytology Immune response Immunodeficiency Laboratories Liver Liver - cytology Liver - embryology Liver transplantation Liver transplants Lymphocytes B Lymphocytes T Mast cells Mast Cells - cytology Medicine and Health Sciences Mice Mice, Transgenic Monocytes Morphogenesis Neonates Ontogeny Population Pregnancy Pregnant women Research and Analysis Methods Rodents Stem cell transplantation Stem cells Transplantation Transplants & implants U-Plasminogen activator Urokinase Urokinase-Type Plasminogen Activator - genetics |
| title | The adult livers of immunodeficient mice support human hematopoiesis: evidence for a hepatic mast cell population that develops early in human ontogeny |
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