Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors
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{"title"=>"Growth factor-activated stem cell circuits and stromal signals cooperatively accelerate non-integrated iPSC reprogramming of human myeloid progenitors", "type"=>"journal", "authors"=>[{"first_name"=>"Tea Soon", "last_name"=>"Park", "scopus_author_id"=>"20735055400"}, {"first_name"=>"Jeffrey S.", "last_name"=>"Huo", "scopus_author_id"=>"7006240233"}, {"first_name"=>"Ann", "last_name"=>"Peters", "scopus_author_id"=>"56268447000"}, {"first_name"=>"C. Conover", "last_name"=>"Talbot", "scopus_author_id"=>"7102656875"}, {"first_name"=>"Karan", "last_name"=>"Verma", "scopus_author_id"=>"35485879700"}, {"first_name"=>"Ludovic", "last_name"=>"Zimmerlin", "scopus_author_id"=>"35799348800"}, {"first_name"=>"Ian M.", "last_name"=>"Kaplan", "scopus_author_id"=>"36933104400"}, {"first_name"=>"Elias T.", "last_name"=>"Zambidis", "scopus_author_id"=>"6508030369"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"365400254", "sgr"=>"84864674570", "doi"=>"10.1371/journal.pone.0042838", "scopus"=>"2-s2.0-84864674570", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22905176"}, "id"=>"f7492378-a126-346a-ba41-cc58008ecd64", "abstract"=>"Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (~0.001%-0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ~50% in purified episome-expressing cells. Lineage-committed CD33(+)CD45(+)CD34(-) myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG(+)TRA-1-81(+) hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NFκB signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self-renewal and differentiation in both hematopoietic progenitors and ESC.", "link"=>"http://www.mendeley.com/research/growth-factoractivated-stem-cell-circuits-stromal-signals-cooperatively-accelerate-nonintegrated-ips", "reader_count"=>56, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>18, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>2, "Researcher"=>18, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>16, "Student > Postgraduate"=>4, "Student > Master"=>5, "Other"=>1, "Student > Bachelor"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>33, "Medicine and Dentistry"=>11, "Chemistry"=>3, "Earth and Planetary Sciences"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>11}, "Chemistry"=>{"Chemistry"=>3}, "Earth and Planetary Sciences"=>{"Earth and Planetary Sciences"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>33}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"United States"=>3, "Japan"=>1, "Brazil"=>1}, "group_count"=>1}

Scopus | Further Information

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  • {"files"=>["https://ndownloader.figshare.com/files/594545"], "description"=>"<p>(<b>a</b>) Illumina microarray expressions of ESC-like gene modules (MYC, PRC1, PRC2, and Core; see <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b> for gene lists). Shown are donor cell populations with (+) and without (−) 4F episomal nucleofections, and with (+) and without (−) BMSC-priming: adult fibroblasts (F), Day -3 unstimulated CB cells (D-3 CB), Day 0 FTK GF-stimulated CB cells (D0), Day 3+/− BMSC-primed (D3), and bulk Day 23 early CB-iPSC culture (D23 iPSC). These early D23 iPSC populations were already composed of >50–60% populations with fully-reprogrammed TRA-1-81<sup>+</sup>NANOG<sup>+</sup> phenotypes. Undifferentiated H9 hESC samples served as control (hESC). Module expressions represent log2 mean-subtracted normalized values of signal intensities from averaged, independent biological replicate microarray samples (n = 3 per condition). Although they possessed a transcriptionally inactive Core module, day 0 GF-activated CB progenitors expressed active ESC and MYC modules, and inactive PRC1, and PRC2 modules at mean expression levels that were already comparable to levels in hESC. The annotation and references of all genes in each module is provided in <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b>. (<b>b</b>) Partially reprogrammed ESC module <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Wong1\" target=\"_blank\">[26]</a> expression in CB progenitors. Legend for each sample is the same as above. Unsupervised hierarchical clustering heatmaps of (<b>b</b>) expression and (<b>c</b>) Box plots of log2 mean-normalized values of the ESC module gene signal intensities in somatic target populations, hESC, and reprogrammed cell lines. The heatmap’s color scale was chosen to emphasize subtle mid-range change. The resulting values emphasize relative expression across cell types rather than relative absolute expression across genes. This box and whisker plots (right panels) depict the log2 mean-subtracted normalized values of signal intensities of genes comprising the module set for each cell type indicated from Illumina array data. The top and bottom of a box mark the 75<sup>th</sup> and 25<sup>th</sup> percentile log2 signal values, respectively, while the bar at the middle denotes the median. The whiskers above and below each box mark the upper 90<sup>th</sup> and lower 10<sup>th</sup> percentiles. Paired tests with significance <i>p</i><0.05 (*) or without significance (<i>NS</i>; p>0.05) with values of control hESC are indicated.</p>", "links"=>[], "tags"=>["reprogrammed", "modules", "gf-activated", "cb", "myeloid", "progenitors", "reconfigured", "hesc-like"], "article_id"=>265024, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g004", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Partially_reprogrammed_stem_cell_modules_in_GF_activated_CB_myeloid_progenitors_are_rapidly_reconfigured_to_hESC_like_patterns_/265024", "title"=>"Partially reprogrammed stem cell modules in GF-activated CB myeloid progenitors are rapidly reconfigured to hESC-like patterns.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:23:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/594670"], "description"=>"<p>(<b>a</b>) Unsupervised hierarchical clustering heatmap of expression of the OCT4 interactome module <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Ding1\" target=\"_blank\">[24]</a> (<b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b>) in fibroblasts (F), CB progenitors at various stages of the reprogramming protocol (D-3, D0, D3+/− BMSC), day 23 bulk early CB-iPSC cultures (D23 iPSC), and hESC (H9) controls. Gene arrays samples (<i>n</i> = 3 per condition) are the same as defined above. Box and whisker plots of same samples of the log2 mean-subtracted normalized values of signal intensities of gene module sets for (<b>b</b>) a subset of the OCT4 interactome consisting of ESC-regulating epigenetic modulators <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Ding1\" target=\"_blank\">[24]</a> (see <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b> for list), (<b>c</b>) the MYC transcription factor complex <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Kim3\" target=\"_blank\">[27]</a> (<i>N-MYC, C-MYC, E2F4, E2F1, ZFX, MAX</i>), and (<b>d</b>) the PRC2 repressive complex <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Lee1\" target=\"_blank\">[32]</a> (<i>JARID2, MTF2, EZH2, RBBP4, EPC2, EPC1, SUZ12, EED, EZH1, JARID1A, RBBP7, PHF19, PHF1</i>).</p>", "links"=>[], "tags"=>["progenitors", "oct4-associated", "chromatin", "remodeling", "factors", "augment", "ipsc"], "article_id"=>265155, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g005", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GF_activated_progenitors_expressed_an_active_OCT4_associated_network_as_well_as_chromatin_remodeling_factors_known_to_augment_iPSC_generation_/265155", "title"=>"GF-activated progenitors expressed an active OCT4-associated network as well as chromatin remodeling factors known to augment iPSC generation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:25:55"}
  • {"files"=>["https://ndownloader.figshare.com/files/594388"], "description"=>"<p>Relative expressions of genes in chromatin remodeling factors in parental donor samples. (<b>a</b>) MYC complex regulators, (<b>b</b>) PRC2 complex regulators, (<b>c</b>) Trithorax complex regulators, (<b>d</b>) SWI/SWF family regulators, and (<b>e</b>) Chromodomain (CHD) regulators in day 0 GF-activated CB; pooled CB donors; <i>n</i> = 3 samples), adult fibs (adFibs; <i>n</i> = 3 samples), and hESC (<i>n</i> = 5 samples). Heatmaps and adjacent boxplots show log2 mean-subtracted normalized values of signal intensities from averaged, independent biological replicate microarray samples (n = 3–5 per condition) averages of values, with *p<0.05 where indicated. In mean normalization, each gene’s mean log2 signal value is determined for all the cell types, and then subtracted from each cell type’s signal intensity value for that gene.</p>", "links"=>[], "tags"=>["chromatin", "remodeling", "factors", "augment", "Reprogramming"], "article_id"=>264875, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g003", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Endogenous_expression_of_chromatin_remodeling_factors_known_to_augment_reprogramming_efficiency_in_parental_donor_cells_/264875", "title"=>"Endogenous expression of chromatin remodeling factors known to augment reprogramming efficiency in parental donor cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:21:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/313221", "https://ndownloader.figshare.com/files/313281", "https://ndownloader.figshare.com/files/313336", "https://ndownloader.figshare.com/files/313408", "https://ndownloader.figshare.com/files/313465", "https://ndownloader.figshare.com/files/313642", "https://ndownloader.figshare.com/files/313714", "https://ndownloader.figshare.com/files/313817", "https://ndownloader.figshare.com/files/313887", "https://ndownloader.figshare.com/files/313970", "https://ndownloader.figshare.com/files/314039", "https://ndownloader.figshare.com/files/314099", "https://ndownloader.figshare.com/files/314131", "https://ndownloader.figshare.com/files/314164"], "description"=>"<div><p>Nonviral conversion of skin or blood cells into clinically useful human induced pluripotent stem cells (hiPSC) occurs in only rare fractions (∼0.001%–0.5%) of donor cells transfected with non-integrating reprogramming factors. Pluripotency induction of developmentally immature stem-progenitors is generally more efficient than differentiated somatic cell targets. However, the nature of augmented progenitor reprogramming remains obscure, and its potential has not been fully explored for improving the extremely slow pace of non-integrated reprogramming. Here, we report highly optimized four-factor reprogramming of lineage-committed cord blood (CB) myeloid progenitors with bulk efficiencies of ∼50% in purified episome-expressing cells. Lineage-committed CD33<sup>+</sup>CD45<sup>+</sup>CD34<sup>−</sup> myeloid cells and not primitive hematopoietic stem-progenitors were the main targets of a rapid and nearly complete non-integrated reprogramming. The efficient conversion of mature myeloid populations into NANOG<sup>+</sup>TRA-1-81<sup>+</sup> hiPSC was mediated by synergies between hematopoietic growth factor (GF), stromal activation signals, and episomal Yamanaka factor expression. Using a modular bioinformatics approach, we demonstrated that efficient myeloid reprogramming correlated not to increased proliferation or endogenous Core factor expressions, but to poised expression of GF-activated transcriptional circuits that commonly regulate plasticity in both hematopoietic progenitors and embryonic stem cells (ESC). Factor-driven conversion of myeloid progenitors to a high-fidelity pluripotent state was further accelerated by soluble and contact-dependent stromal signals that included an implied and unexpected role for Toll receptor-NFκB signaling. These data provide a paradigm for understanding the augmented reprogramming capacity of somatic progenitors, and reveal that efficient induced pluripotency in other cell types may also require extrinsic activation of a molecular framework that commonly regulates self-renewal and differentiation in both hematopoietic progenitors and ESC.</p> </div>", "links"=>[], "tags"=>["factor-activated", "circuits", "stromal", "signals", "cooperatively", "non-integrated", "ipsc", "Reprogramming", "myeloid", "progenitors"], "article_id"=>121773, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0042838.s001", "https://dx.doi.org/10.1371/journal.pone.0042838.s002", "https://dx.doi.org/10.1371/journal.pone.0042838.s003", "https://dx.doi.org/10.1371/journal.pone.0042838.s004", "https://dx.doi.org/10.1371/journal.pone.0042838.s005", "https://dx.doi.org/10.1371/journal.pone.0042838.s006", "https://dx.doi.org/10.1371/journal.pone.0042838.s007", "https://dx.doi.org/10.1371/journal.pone.0042838.s008", "https://dx.doi.org/10.1371/journal.pone.0042838.s009", "https://dx.doi.org/10.1371/journal.pone.0042838.s010", "https://dx.doi.org/10.1371/journal.pone.0042838.s011", "https://dx.doi.org/10.1371/journal.pone.0042838.s012", "https://dx.doi.org/10.1371/journal.pone.0042838.s013", "https://dx.doi.org/10.1371/journal.pone.0042838.s014"], "stats"=>{"downloads"=>40, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Growth_Factor_Activated_Stem_Cell_Circuits_and_Stromal_Signals_Cooperatively_Accelerate_Non_Integrated_iPSC_Reprogramming_of_Human_Myeloid_Progenitors/121773", "title"=>"Growth Factor-Activated Stem Cell Circuits and Stromal Signals Cooperatively Accelerate Non-Integrated iPSC Reprogramming of Human Myeloid Progenitors", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-08-08 00:29:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/594302"], "description"=>"<p>(<b>a</b>) Schematic summarizes the experimental strategy for determining 4F reprogramming efficiencies of FACS-purified hematopoietic progenitors of (<b>b</b>) BMSC-primed lineage-committed or (<b>c</b>) +/− BMSC-primed transgene-enriched myeloid populations. Experimental details are provided in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#s4\" target=\"_blank\">Materials and Methods</a>. The %CD34<sup>+</sup> gradient symbol above the schematic reflects the concept that multipotent primitive CD34+CD38lo stem-progenitors are enriched during Days -3 to -2, but differentiate rapidly in culture thereafter (see also <b>Fig... </b><b>1c</b> and <b>Fig... </b><b>S2a)</b>. CD34<sup>+</sup>CD38<sup>lo</sup> stem-progenitors give rise to lineage-committed CD34<sup>+</sup>CD38<sup>+</sup> progenitors which subsequently differentiate further to CD34-negative CD33<sup>+</sup>CD45<sup>+</sup> myeloid cells (<i>e.g</i>., promyelocytes). Post-sort analysis of FACS-purified Day 0 CD34<sup>+</sup>CD38<sup>+</sup> CB fractions verified that >95% of this populations consisted of CD33<sup>+</sup>CD13<sup>+</sup>CD45<sup>+</sup> myeloid cells (see also <b>Fig... </b><b>1c</b>). Both reprogramming efficiency (AP and live TRA-1-81 staining of hESC-like colonies) and reprogramming completion (bulk SSEA4<sup>+</sup>TRA-1-81<sup>+</sup> and NANOG<sup>+</sup> FACS staining) assays were conducted 4 weeks following 4F nucleofections on P<sub>0</sub> MEF cultures. (<b>b</b>) Shown is a representative AP staining (plates done in triplicate, with indicated average number of hESC-like colonies emerging per the number of single sorted day 3 BMSC-primed CB cells plated on MEF (i.e., unsorted CB <i>vs.</i> CD34<sup>+</sup>CD38<sup>lo </sup><i>vs.</i> CD34<sup>+</sup>CD38<sup>+</sup> fractions. The averaged results of two independent experiments are indicated. In lower panels are shown representative FACS staining of surface TRA-1-81 and intracellular NANOG pluripotency markers of the same cultures demonstrating that 50–80% of AP<sup>+</sup> hESC-like colonies possessed a Type III TRA-1-81<sup>+</sup>NANOG<sup>+</sup> phenotype <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Chan1\" target=\"_blank\">[43]</a>. (<b>c</b>) To determine the more accurate reprogramming efficiency of purified +/− BMSC-primed episome-expressing myeloid populations, CB progenitors were co-nucleofected on day 0 with <i>both</i> the 4F pEP4 EO2S EM2K episome, as well as a pCEP4-GFP episomal GFP reporter construct. Episomal transgene expressing-only populations were subsequently FACS-purified by GFP expression prior to plating on day 3 MEF following with (+BMSC) or without (-BMSC) stromal co-culture. This was done by staining +/− BMSC-primed CB cells on day 3 with CD34-PE and FACS-purifying them into episome-expressing (GFP<sup>+</sup>CD34<sup>+</sup>, GFP<sup>+</sup>CD34<sup>−</sup>), and non episome-expressing (GFP<sup>−</sup>) populations prior to MEF plating. The results of AP stained plates shown are representative of independent sorting experiments using pooled donor CB samples for each 4F nucleofection, with the averaged results of two independent experiments indicated below. FACS analysis of these same experiments (data not shown) revealed 60% TRA-1-81 and NANOG expression for +BMSC AP<sup>+</sup> colonies (GFP<sup>+</sup>CD34<sup>−</sup>), and 55% TRA-1-81 expression for –BMSC AP<sup>+</sup> colonies (GFP<sup>+</sup>CD34<sup>−</sup>).</p>", "links"=>[], "tags"=>["4f", "Reprogramming", "facs-purified", "hematopoietic"], "article_id"=>264784, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g002", "stats"=>{"downloads"=>1, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Episomal_4F_reprogramming_of_FACS_purified_hematopoietic_populations_/264784", "title"=>"Episomal 4F reprogramming of FACS-purified hematopoietic populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:19:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/594792"], "description"=>"<p>(<b>a</b>) 7F (SOKMNLT) reprogramming efficiencies of developmentally progressing BMSC-primed GF-activated Day 0 progenitors were determined with AP<sup>+</sup> staining staining of ESC-like colonies, at P<sub>1</sub>, 25 days following 7F nucleofections. BMSC-primed Day 0 CD34+ hematopoietic progenitors (FL, CB, mPB, BM), keratinocytes (KER), or fetal fibroblasts (FFB) populations were reprogrammed with non-integrated 7F episomes as described in text. Log2 mean-normalized microarray expressions (signal intensities) in somatic target populations (from pooled Day 0 GF-primed CD34<sup>+</sup> donors; n = 3–4 per sample) and H9 hESC of (<b>b</b>) MYC complex regulator genes, (<b>c</b>) MYC module, (<b>d</b>) MYC-regulated ESC module, and (<b>e</b>) OCT4 interactome gene module (see <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b> for gene module members).</p>", "links"=>[], "tags"=>["developmentally", "progressed", "gf-activated", "hematopoietic", "progenitors", "correlates", "levels", "esc-like"], "article_id"=>265269, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g006", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reprogramming_efficiency_in_developmentally_progressed_GF_activated_hematopoietic_progenitors_is_predicted_by_and_directly_correlates_with_expression_levels_of_ESC_like_circuits_/265269", "title"=>"Reprogramming efficiency in developmentally progressed GF-activated hematopoietic progenitors is predicted by and directly correlates with expression levels of ESC-like circuits.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:27:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/595021"], "description"=>"<p>MYC; MYC-regulated ESC and MYC gene modules, OCT4-I; OCT4 interactome gene module, PcG-regulated targets; PRC1, PRC2 gene modules, Core; SOX2-OCT4-NANOG-regulated gene module (see <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s012\" target=\"_blank\">Table S1</a></b> for gene lists that comprise each module). Day 0 GF-activated CB progenitors expressed <i>de novo</i> activated MYC and OCT4-I (but not Core) gene modules and inactivated PcG-regulated modules (PRC1, PRC2) at hESC-like levels. These networks were subsequently facilitated to a stable pluripotent state (and a completion of reprogramming of the Core module) via synergies between stromal signals and transient episomal expression of the Yamanaka factors.</p>", "links"=>[], "tags"=>["episomal", "Reprogramming", "myeloid", "progenitors", "mediated", "synergies", "extrinsic", "stromal", "signals", "gf", "activation", "reprogrammed", "esc-like"], "article_id"=>265497, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g008", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Efficient_episomal_reprogramming_of_human_myeloid_progenitors_is_mediated_by_synergies_between_extrinsic_stromal_signals_and_the_GF_activation_of_partially_reprogrammed_ESC_like_gene_modules_/265497", "title"=>"Efficient episomal reprogramming of human myeloid progenitors is mediated by synergies between extrinsic stromal signals and the GF activation of partially reprogrammed ESC-like gene modules.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:31:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/594889"], "description"=>"<p>(<b>a</b>) Emergence of surface pluripotency markers (SSEA4, TRA-1-81) were assayed by FACS at 3 weeks in bulk cultures of 4F episomally-reprogrammed somatic cells briefly co-cultured with (+) or without (<b>−</b>) irradiated BMSC (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s001\" target=\"_blank\"><b>Fig.... </b><b>S1</b></a>). Fetal fibroblasts (FFB), adult fibroblasts (AdFib), adult keratinocytes (Ker), and GF-activated Day 0 CB (CB) were nucleofected with 4F or 7F on Day 0 (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s001\" target=\"_blank\"><b>Fig.... </b><b>S1</b></a>), and reprogrammed bulk cultures were analyzed by FACS 3 weeks later. AP stains of hESC-like colonies were done in parallel of these same experiments, and are presented in <b>Fig.... </b><b>1d</b>. Shown are the averaged results of 2–5 experiments with averages, and significances (<b>*</b>) designated at peak of bar graphs. (<b>b,c</b>) The kinetics of pluripotency marker emergence of 4F reprogrammed CB progenitors with (+) and without (−) BMSC priming. (<b>b</b>) SSEA4<sup>+</sup>, and (<b>c</b>) SSEA4<sup>+</sup>TRA-1-60<sup>+</sup> expressions. (<b>d</b>) Enhancement of 4F CB reprogramming with (+BMSC) and without (- BMSC) stromal priming was due to signals that were partially cell contact-dependent, and partially soluble factor-mediated. GF-activated CB cells were cultured as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s001\" target=\"_blank\"><b>Fig.... </b><b>S1</b></a> from Day 0 until Day 3 without BMSC co-culture (-BMSC), with BMSC co-culture (+BMSC), or with BMSC co-culture but physically separated from CB cells with a Transwell insert that prevented cell-cell contact between BMSC and CB cells, but allowed diffusion of soluble stromal factors (+BMSC (T)). Shown is the relative fold-increase of reprogramming efficiency (enumerated AP+ hESC-like colonies) from two averaged 4F-reprogramming experiments from baseline efficiencies (-BMSC conditions). Reprogramming efficiency was determined at 3 weeks post-nucleofection with 4F, determined by AP staining of hESC-like colonies (as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#s4\" target=\"_blank\">Methods</a>). (<b>e</b>) Gene specific enrichment analysis (GSEA) computation of pathways activated in 4F-nucleofected CB cells by stromal signals. The GSEA algorithm was used to identify curated pathways over-represented among genes with significant (p<0.05, FDR<0.05) differential expression between Day 3 (D3) +BMSC-primed CB samples, <i>vs</i>. D3 unprimed (-BMSC) CB samples that were nucleofected at Day 0 with 4F episome. <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s014\" target=\"_blank\">Table S3</a></b> summarizes the MSigDB v. 3.0 gene set categories that were enriched with FDR <0.05 and nom <i>p</i><0.05 for these two paired gene set computations. Shown in (<b>e</b>) are the major categories of enriched pathways that were significantly and differentially activated in Day 3 BMSC-primed and 4F-nucleofected CB samples.</p>", "links"=>[], "tags"=>["Reprogramming", "was", "further", "accelerated", "paracrine", "contact-dependent", "stromal"], "article_id"=>265374, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g007", "stats"=>{"downloads"=>3, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Episomal_reprogramming_was_further_accelerated_by_paracrine_and_contact_dependent_stromal_signals_/265374", "title"=>"Episomal reprogramming was further accelerated by paracrine and contact-dependent stromal signals.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:29:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/594209"], "description"=>"<p>The role of a brief 3-day BMSC co-culture of GF-activated CD34<sup>+</sup> CB progenitors following a single pulse of episomal plasmids on Day 0, and the number of episomal factors required for efficient reprogramming. The experimental design is summarized in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s001\" target=\"_blank\"><b>Fig. S1</b></a>. (<b>a</b>) Soluble factors from brief BMSC co-culture preserved the viability of GF-activated CB progenitors. Viable CB cells were enumerated via Trypan Blue on Day 3 following nucleofection with four episomal factors (SOX2, OCT4, KLF4, MYC; 4F) on Day 0. Shown are the fold-increases of GF-treated CD34<sup>+</sup> CB cells from Day 0 to Day 3 that resulted from: no BMSC co-culture (-BMSC), with irradiated BMSC co-culture (+BMSC), or with BMSC co-culture but separated by a Transwell insert (BMSC (T)). The Transwell culture insert prevented cell-cell contact between BMSC and CB cells, but allowed soluble stromal factors to diffuse freely to the cultured CB cells. Averages, SEM, and <i>p</i> values (Students t test) of <i>n</i> = 4 averaged experiments is shown. <i>NS</i> = not significant (<i>p</i>>0.05). (<b>b</b>) Brief co-culture of GF-activated CB cells with irradiated BMSC (+BMSC) did not increase the frequency of cells in G1 or S cell cycle phases at Day 3 (D3) of the reprogramming protocol (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s001\" target=\"_blank\"><b>Fig. S1</b></a>) compared to GF alone (-BMSC). CB cells were nucleofected on Day 0 (D0) with 4F or 7F plasmids, or nucleofected with Amaxa buffer only (Mock). Cell cycle status of stromal-activated D3 CB, DO (pre-nucleofected) control CB cells, and adult fibroblasts (HDF1, HUF5; nucleofected with 7F) was determined on Day 3 of reprogramming protocols via FACS analysis of EdU incorporation and DNA content (7AAD), as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#s4\" target=\"_blank\">Methods</a>. Cells in G1 phase were defined as being EdU negative and 7AAD(2n); % cells in S phase were determined by gating on EdU positive 7AAD (2n+) populations. Data shown is the average of 2 experiments from individual batches of pooled CB donors run in triplicate. (<b>c</b>) GF-activated CB cells consist of a relatively homogenous myeloid population. By Day 3 of the reprogramming protocol (following +/− BMSC co-culture), both CD34<sup>+</sup> and CD34<sup>−</sup> GF-activated CD45<sup>+</sup> CB progenitors had differentiated to primarily a myeloid CD33<sup>+</sup> and CD13<sup>+</sup> (not shown) phenotype. (<b>d</b>) Episomal reprogramming efficiencies of various somatic targets with either four factors (4F; SOKM, on a single plasmid, pEP4 EO2S EM2K) or seven factors (7F; SOKMNLT, on three separate plasmids), and with (+) or without (−) BMSC priming were determined by rapid AP staining (in triplicate) at 3 weeks following episomal nucleofections for CB progenitors (CB), fetal fibroblasts (FFB), adult fibroblasts (AdFib), and adult keratinocytes (Ker). Reprogramming efficiencies for emergence of Type III hiPSC <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838-Subramanian1\" target=\"_blank\">[45]</a> were quantitated in some experiments with parallel live TRA-1-81 staining, which gave similar results to enumeration of AP<sup>+</sup> hESC-like colonies (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone.0042838.s003\" target=\"_blank\"><b>Fig. S3</b></a>). By 3 weeks post 4F nucleofections, the majority of AP<sup>+</sup> hESC-like colonies had already converted with extremely high efficiencies to 50–80% fully reprogrammed SSEA4<sup>+</sup>TRA-1-81<sup>+</sup>NANOG<sup>+</sup> Type III hiPSC (see also <b><a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0042838#pone-0042838-g007\" target=\"_blank\">Fig. 7a</a></b>). Each condition presented was repeated at least two to five times, as indicated, and with significance (t test; * = <i>p</i><0.05) as indicated. 4F SOKM reprogramming of CB progenitors was even more robust than with equimolar DNA quantities of the 7F three-plasmid system (albeit initially less rapid). ND; BMSC co-culture was not done. With omission of the brief BMSC activation step, rarer (∼10–150-fold less) and slower-emerging CB-iPSC were produced with single-plasmid 4F nucleofections, but at frequencies that were still significantly greater than 7F reprogramming of fetal and adult fibroblasts, or adult keratinocytes.</p>", "links"=>[], "tags"=>["co-culture", "primed", "non-integrated", "Reprogramming", "cb", "progenitors", "episomal", "yamanaka", "factors"], "article_id"=>264683, "categories"=>["Biological Sciences", "Genetics", "Developmental Biology"], "users"=>["Tea Soon Park", "Jeffrey S. Huo", "Ann Peters", "C. Conover Talbot Jr.", "Karan Verma", "Ludovic Zimmerlin", "Ian M. Kaplan", "Elias T. Zambidis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0042838.g001", "stats"=>{"downloads"=>1, "page_views"=>36, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BMSC_co_culture_primed_efficient_non_integrated_reprogramming_of_CB_progenitors_that_required_only_four_episomal_Yamanaka_factors_on_a_single_plasmid_/264683", "title"=>"BMSC co-culture primed efficient non-integrated reprogramming of CB progenitors that required only four episomal Yamanaka factors on a single plasmid.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-08-08 01:18:03"}

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Relative Metric

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