In Vitro Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells
Publication Date
October 21, 2015
Journal
PLOS ONE
Authors
Sarada Devi Ramachandran, Katharina Schirmer, Bernhard Münst, Stefan Heinz, et al
Volume
10
Issue
10
Pages
e0139345
DOI
https://dx.plos.org/10.1371/journal.pone.0139345
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0139345
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26488607
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619350
Europe PMC
http://europepmc.org/abstract/MED/26488607
Web of Science
000363248400027
Scopus
84949466262
Mendeley
http://www.mendeley.com/research/vitro-generation-functional-liver-organoidlike-structures-using-adult-human-cells-1
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Mendeley | Further Information

{"title"=>"In vitro generation of functional liver organoid-like structures using adult human cells", "type"=>"journal", "authors"=>[{"first_name"=>"Sarada Devi", "last_name"=>"Ramachandran", "scopus_author_id"=>"56995614000"}, {"first_name"=>"Katharina", "last_name"=>"Schirmer", "scopus_author_id"=>"56995773900"}, {"first_name"=>"Bernhard", "last_name"=>"Münst", "scopus_author_id"=>"6506995653"}, {"first_name"=>"Stefan", "last_name"=>"Heinz", "scopus_author_id"=>"23034376500"}, {"first_name"=>"Shahrouz", "last_name"=>"Ghafoory", "scopus_author_id"=>"55151130400"}, {"first_name"=>"Stefan", "last_name"=>"Wölfl", "scopus_author_id"=>"7004635378"}, {"first_name"=>"Katja", "last_name"=>"Simon-Keller", "scopus_author_id"=>"36522087000"}, {"first_name"=>"Alexander", "last_name"=>"Marx", "scopus_author_id"=>"55798019600"}, {"first_name"=>"Cristina Ionica", "last_name"=>"Oie", "scopus_author_id"=>"23501574100"}, {"first_name"=>"Matthias P.", "last_name"=>"Ebert", "scopus_author_id"=>"35239660600"}, {"first_name"=>"Heike", "last_name"=>"Walles", "scopus_author_id"=>"35957223600"}, {"first_name"=>"Joris", "last_name"=>"Braspenning", "scopus_author_id"=>"7004638097"}, {"first_name"=>"Katja", "last_name"=>"Breitkopf-Heinlein", "scopus_author_id"=>"36863175300"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84949466262", "issn"=>"19326203", "pmid"=>"26488607", "pui"=>"607159087", "doi"=>"10.1371/journal.pone.0139345", "sgr"=>"84949466262"}, "id"=>"b4688b26-2322-3f95-87eb-af98942769d4", "abstract"=>"In this study we used differentiated adult human upcyte® cells for the in vitro generation of liver organoids. Upcyte® cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte® process). Proliferating upcyte® cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte® cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured in vitro on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated in vitro. They can be cultured for a prolonged period of time and are potentially useful ex vivo models to study liver functions.", "link"=>"http://www.mendeley.com/research/vitro-generation-functional-liver-organoidlike-structures-using-adult-human-cells-1", "reader_count"=>69, "reader_count_by_academic_status"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Other"=>8, "Student > Master"=>14, "Student > Bachelor"=>9, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>4, "Professor > Associate Professor"=>3, "Researcher"=>12, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>14, "Other"=>8, "Student > Master"=>14, "Student > Bachelor"=>9, "Professor"=>2}, "reader_count_by_subject_area"=>{"Engineering"=>6, "Unspecified"=>7, "Biochemistry, Genetics and Molecular Biology"=>14, "Materials Science"=>1, "Agricultural and Biological Sciences"=>21, "Medicine and Dentistry"=>13, "Neuroscience"=>1, "Pharmacology, Toxicology and Pharmaceutical Science"=>4, "Chemistry"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>6}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>13}, "Neuroscience"=>{"Neuroscience"=>1}, "Chemistry"=>{"Chemistry"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>21}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>14}, "Unspecified"=>{"Unspecified"=>7}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>4}}, "reader_count_by_country"=>{"Italy"=>1, "Germany"=>1}, "group_count"=>4}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2368495"], "description"=>"<p>Phase contrast photographs and immuno-fluorescent stainings for specific cell type markers in the three different types of upcyte<sup>®</sup> cells which were used for liver organoid generation. CK: Cytokeratin.</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582180, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g001", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Appearance_of_the_cells_used_for_organoid_formation_/1582180", "title"=>"Appearance of the cells used for organoid formation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368498"], "description"=>"<p>(A) Time-dependent formation of liver organoids in 24-well plates. Long-term culture (>48h) was performed in a dynamic system, e.g. the quasi vivo system from kirkstall<sup>®</sup> (B) or the Live-box 1 system, generated by the group of Prof. Arti Ahluwalia, Faculty of Engineering, University of Pisa, Italy (C).</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582183, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g002", "stats"=>{"downloads"=>4, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Generation_of_liver_organoids_in_vitro_/1582183", "title"=>"Generation of liver organoids <i>in vitro</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368504"], "description"=>"<p>H&E- and immuno-stainings for cell-type markers were performed in serial sections of liver organoids (LO) after 72h and 10 days of culture. The scale bars for the original magnification of 200x equals 200 μm, that of the original magnification of 100x equals 500 μm.</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582189, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spatial_distribution_of_the_different_cell_types_within_the_liver_organoids_/1582189", "title"=>"Spatial distribution of the different cell types within the liver organoids.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368510"], "description"=>"<p>mRNA transcripts of the indicated genes were detected by <i>in situ</i> hybridization in serial sections of liver organoids (LO) after 72h and 10 days of culture.</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582195, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g004", "stats"=>{"downloads"=>0, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_functional_genes_and_hepatocyte_markers_on_the_RNA_level_/1582195", "title"=>"Expression of functional genes and hepatocyte markers on the RNA level.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368513"], "description"=>"<p><b>A)</b> Immunofluorescent staining for the epithelial marker protein E-Cadherin (green) and the functional marker protein albumin (red) in a 10-day LO on the left and a cross-section of adult human liver on the right. The scale bar equals 10 μm. <b>B)</b> Immunohistochemical stainings for E-Cadherin and the proliferation marker Ki67 in a 10-day liver organoid (left panel). Human liver sections were used as control (right panel). The arrows point to Ki67-positive cells in the liver. Scale bars equal 100 μm (original magnification: 400x). <b>C)</b> The expression levels of the hepatocyte polarization markers E-Cadherin and ZO–1 as well as albumin were further analyzed by real-time PCR in samples from 10-day LOs (the average value of 4 different LOs +/-SD is shown). For comparison samples from four different donors were analyzed in parallel. Expression of the house-keeping gene HPRT–1 was used for normalization. pHC = primary hepatocytes (non-cultured).</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582197, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g005", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Immunostainings_of_a_10_day_liver_organoid_in_comparison_with_adult_human_liver_/1582197", "title"=>"Immunostainings of a 10-day liver organoid in comparison with adult human liver.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368514"], "description"=>"<p><b>A)</b> The basal activities of Cyps 3A4, 2B6 and 2C9 were measured (average of n = 4 +/-SD) in 10-day liver organoids (LOs). LOs were formed as shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139345#pone.0139345.g002\" target=\"_blank\">Fig 2</a> inside a bioreactor (Quasi-vivo<sup>®</sup> System from Kirkstall). Substrate incubation was performed for 60 min on day 10 of culture. CYP-activity was normalized to total protein content of the organoids. Paired pHC are the same primary hepatocytes which had been upcyted® and used to form the organoids. Basal CYP activity levels of primary cells shown in the figure were provided by the manufacturer. For CYP2C9 no value was given (ND, not determined). <b>B)</b> Three more CYPs as well as Sult1a1 and Ugt1a3 were investigated on the mRNA expression level by real-time PCR. The average values of 4 different LOs +/-SD is shown. For comparison RNA samples from 4 donors were analyzed in parallel. The samples from donor 1–3 were RNAs from hepatocytes which were isolated, frozen down without primary culture and directly lysed after thawing (pHC; non-cultured cells). The sample from donor 4 represents the total RNA isolated from a piece of whole liver. Expression of the house-keeping gene HPRT–1 was used for normalization. <b>C)</b> Cross-sections of a 10-day LO (on the left) in direct comparison to adult human liver (on the right; stained against cytokeratins plus haematoxylin). The rectangles mark representative cells showing the typical cuboidal shape of polarized hepatocytes. The circles highlight areas where hepatocytes have arranged around circular openings. The scale bar equals 100 μm.</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582198, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.g006", "stats"=>{"downloads"=>3, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_and_activity_of_drug_metabolizing_enzymes_Comparison_of_10_day_LOs_with_human_liver_/1582198", "title"=>"Expression and activity of drug metabolizing enzymes. Comparison of 10-day LOs with human liver.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368515"], "description"=>"<p>Gene specific sequences of the primers used for in situ hybridizations.</p>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582199, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345.t001", "stats"=>{"downloads"=>2, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_specific_sequences_of_the_primers_used_for_in_situ_hybridizations_/1582199", "title"=>"Gene specific sequences of the primers used for in situ hybridizations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-10-21 03:37:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/2368516"], "description"=>"<div><p>In this study we used differentiated adult human upcyte<sup>®</sup> cells for the <i>in vitro</i> generation of liver organoids. Upcyte<sup>®</sup> cells are genetically engineered cell strains derived from primary human cells by lenti-viral transduction of genes or gene combinations inducing transient proliferation capacity (upcyte<sup>®</sup> process). Proliferating upcyte<sup>®</sup> cells undergo a finite number of cell divisions, i.e., 20 to 40 population doublings, but upon withdrawal of proliferation stimulating factors, they regain most of the cell specific characteristics of primary cells. When a defined mixture of differentiated human upcyte<sup>®</sup> cells (hepatocytes, liver sinusoidal endothelial cells (LSECs) and mesenchymal stem cells (MSCs)) was cultured <i>in vitro</i> on a thick layer of Matrigel™, they self-organized to form liver organoid-like structures within 24 hours. When further cultured for 10 days in a bioreactor, these liver organoids show typical functional characteristics of liver parenchyma including activity of cytochromes P450, CYP3A4, CYP2B6 and CYP2C9 as well as mRNA expression of several marker genes and other enzymes. In summary, we hereby describe that 3D functional hepatic structures composed of primary human cell strains can be generated <i>in vitro</i>. They can be cultured for a prolonged period of time and are potentially useful <i>ex vivo</i> models to study liver functions.</p></div>", "links"=>[], "tags"=>["cell strains", "study liver functions", "2b", "2c", "40 population doublings", "liver organoids show", "3a", "Adult Human Cells", "msc", "cyp", "lsec"], "article_id"=>1582200, "categories"=>["Uncategorised"], "users"=>["Sarada Devi Ramachandran", "Katharina Schirmer", "Bernhard Münst", "Stefan Heinz", "Shahrouz Ghafoory", "Stefan Wolfl", "Katja Simon-Keller", "Alexander Marx", "Cristina Ionica Øie", "Matthias P. Ebert", "Heike Walles", "Joris Braspenning", "Katja Breitkopf-Heinlein"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0139345", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_Vitro_Generation_of_Functional_Liver_Organoid_Like_Structures_Using_Adult_Human_Cells/1582200", "title"=>"<i>In Vitro</i> Generation of Functional Liver Organoid-Like Structures Using Adult Human Cells", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-10-21 03:37:40"}

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{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}

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