Small molecule-mediated reprogramming of human hepatocytes into bipotent progenitor cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA472040 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7182820_1.fastq.gz | Fastqsanger.gz | |||
| SRR7182820_2.fastq.gz | Fastqsanger.gz | |||
| SRR7182821_1.fastq.gz | Fastqsanger.gz | |||
| SRR7182821_2.fastq.gz | Fastqsanger.gz | |||
| SRR7182822_1.fastq.gz | Fastqsanger.gz |
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Project description:Currently, much effort is directed to the development of new cell sources for clinical therapy using cell fate conversion approaches by small molecules. Direct lineage reprogramming to a progenitor state has been reported in terminally differentiated rodent hepatocytes, yet remains a challenge in human hepatocytes. Human hepatocytes were isolated from healthy and diseased donor livers and reprogrammed into progenitor cells by two small molecules, A83-01 and CHIR99021 (AC), in the presence of EGF and HGF. The stemness properties of human chemically derived hepatic progenitors (hCdHs) were tested by standard in vitro and in vivo assays and transcriptome profiling. We developed a robust culture system for generating hCdHs with therapeutic potential. The use of HGF proved to be an essential determinant of fate conversion process. Based on functional evidence, activation of HGF/MET signal transduction system collaborated with A83-01 and CHIR99021 to allow a rapid expansion of progenitor cells through activation of ERK pathway. hCdHs expressed hepatic progenitor marker genes and proteins, and could self-renew for at least 10 passages while retaining normal karyotype and potential to differentiate into functional hepatocytes and biliary epithelial cells in vitro. RNASeq gene expression profiling confirmed transcriptional reprogramming of hCdHs toward a progenitor state and suppression of mature hepatocyte transcripts. Upon intrasplenic transplantation into immunocompromised mice with acute liver injury, hCdHs effectively repopulated damaged parenchyma. Our study is a first report of successful reprogramming of human hepatocytes to a population of proliferating bipotent cells with regenerative potential. hCdHs may provide a nove tool that permits expansion and genetic manipulation of patient-specific progenitors to study regeneration and repair of diseased liver.
2019-05-08 | GSE114643 | GEO
Project description:A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and if such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01 and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus our study advances the goals of liver regenerative medicine. Transcriptomic analysis for mouse CLiPs at P1 which underwent hepatic induction (Matrix 1). Transcriptomic analysis for mouse CLiPs at P11-12 which underwent hepatic induction (Matrix 2).
2016-11-15 | GSE87579 | GEO
Project description:A challenge for advancing approaches to liver regeneration is loss of functional differentiation capacity when hepatocyte progenitors are maintained in culture. Recent lineage-tracing studies have shown that mature hepatocytes (MHs) convert to an immature state during chronic liver injury, and we investigated whether this conversion could be recapitulated in vitro and if such converted cells could represent a source of expandable hepatocytes. We report that a cocktail of small molecules, Y-27632, A-83-01 and CHIR99021, can convert rat and mouse MHs in vitro into proliferative bipotent cells, which we term chemically induced liver progenitors (CLiPs). CLiPs can differentiate into both MHs and biliary epithelial cells that can form functional ductal structures. CLiPs in long-term culture did not lose their proliferative capacity or their hepatic differentiation ability, and rat CLiPs were shown to extensively repopulate chronically injured liver tissue. Thus our study advances the goals of liver regenerative medicine. Transcriptomic analyses for freshly isolated MHs and cells cultured for the designated periods with or without YAC stimulation (Matrix 1). Transcriptomic analysis for CLiPs which underwent hepatic induction (Matrix 2). Transcriptomic comparison of hepatic inducibility between CLiPs at early passage and those at late passages (Matrix 3). Transcriptomic comparison between chimera-derived rat cells (designated as “2nd”) and primary rat MH-derived cells (designated as “1st”) (Matrix 4).
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Project description:Highly purified subpopulations of primitive bipotent and committed luminal progenitor cells as well as mature luminal and myoepithelial cells from normal human mammary tissue were isolated and compared their transcriptomes obtained using the Affymetrix GeneChip Human X3P Array. Experiment Overall Design: 12 Afffymetrix array hybridizations were performed on RNA samples extracted from highly purified subpopulations of primitive bipotent and committed luminal progenitor cells as well as mature luminal and myoepithelial cells isolate from 3 different normal human mammary tissue.
2008-06-20 | E-GEOD-11394 | biostudies-arrayexpress
Project description:Cell fate can be directly converted between differentiated cells by lineage reprogramming, thus generating multiple cell types across developmental lineages. However, lineage reprogramming is hindered by incomplete cell-fate conversion with residual initial cell identity and partial functions compared with the native counterparts. Here, we develop a high-fidelity reprogramming strategy, by mimicking the natural cell-fate changing route, thus permitting the production of functionally competent human hepatocytes from another cell type. We first converted fibroblasts into plastic hepatic progenitor-like cells (hHPLCs) and chemically induced them into mature hepatocytes. The molecular identity of human induced hepatocytes (hiHeps) are suggested a terminally differentiated state, resembling primary human hepatocytes (PHHs). Functionally, hiHeps were competent to replace PHHs for equivalent drug-metabolizing activities, toxicity prediction and hepatitis B virus infection. Remarkably, the stably robust expansion of hHPLCs allowed large-scale generation of mature hepatocytes. Our results demonstrate the necessity of taking a reprogramming step for plastic progenitors for efficient cell-fate conversion. This strategy is promising for the generation of other mature human cell types.
2019-09-02 | GSE112330 | GEO
Project description:To identify the molecular mechanisms and environmental inducers contributing to reprogramming of hepatocytes into progenitors in HCC context, we used the HepaRG cell line as model. We performed transcriptomic analysis at various time-points during this process; 0h, 1h, 4h, 8h, 12h, 16h, 24h and 48h.
2013-12-05 | E-GEOD-52989 | biostudies-arrayexpress
Project description:Human distal lung maps and lineage hierarchies reveal a bipotent progenitor
| PRJNA738597 | ENA
Project description:To identify the molecular mechanisms and environmental inducers contributing to reprogramming of hepatocytes into progenitors in HCC context, we used the HepaRG cell line as model.
2013-12-05 | GSE52989 | GEO
Project description:Cell fate can be directly converted between differentiated cells by lineage reprogramming, thus generating multiple cell types across developmental lineages. However, lineage reprogramming is hindered by incomplete cell-fate conversion with residual initial cell identity and partial functions compared with the native counterparts. Here, we develop a high-fidelity reprogramming strategy, by mimicking the natural cell-fate changing route, thus permitting the production of functionally competent human hepatocytes from another cell type. We first converted fibroblasts into plastic hepatic progenitor-like cells (hHPLCs) and chemically induced them into mature hepatocytes. The molecular identity of human induced hepatocytes (hiHeps) are suggested a terminally differentiated state, resembling primary human hepatocytes (PHHs). Functionally, hiHeps were competent to replace PHHs for equivalent drug-metabolizing activities, toxicity prediction and hepatitis B virus infection. Remarkably, the stably robust expansion of hHPLCs allowed large-scale generation of mature hepatocytes. Our results demonstrate the necessity of taking a reprogramming step for plastic progenitors for efficient cell-fate conversion. This strategy is promising for the generation of other mature human cell types.
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Project description:We analyzed gene expression of hepatocytic parental progenitor cells in a population of small hepatocytes. The hepatocytic parental progenitor cells possess self-renewal capability. These cells maintain the ability to differentiate into mature hepatocytes.
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