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InVERT molding for scalable control of tissue micro-architecture

ABSTRACT: Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiologic studies and tissue therapies. Here, we present an ‘Intaglio-Void/Embed-Relief Topographic (InVERT) molding’ method for microscale organization of many cell types, including induced pluripotent stem cell (iPS)-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical biologic studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or iPS-derived hepatocytes and hepatic compartment microstructure and cellular composition modulate hepatic functions. Configurations found to be optimal in vitro also result in superior survival and function after transplantation into mice, demonstrating the importance of architectural optimization prior to implantation. Two replicates of iPS-Hepatocytes cultured alone for 1 day or co-cultured with mouse J2 stromal cells for 1 day. One replicate of a mixture of iPS-Hepatocytes cultured alone for 1 day and then combined with J2 stromal cell RNA after RNA purification. Pure J2 stromal cell RNA was also hybridized to they Human chips but those hybridizations did not produce usable data and have not been included in this study.

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Whittaker

PROVIDER: E-GEOD-43309 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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InVERT molding for scalable control of tissue micro-architecture

Project description:Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiologic studies and tissue therapies. Here, we present an ‘Intaglio-Void/Embed-Relief Topographic (InVERT) molding’ method for microscale organization of many cell types, including induced pluripotent stem cell (iPS)-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre-clinical, and clinical biologic studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or iPS-derived hepatocytes and hepatic compartment microstructure and cellular composition modulate hepatic functions. Configurations found to be optimal in vitro also result in superior survival and function after transplantation into mice, demonstrating the importance of architectural optimization prior to implantation.

2015-01-04 | GSE43309 | GEO

Hepatocytes :MH vs. ProliHH vs. PHH vs. HLC

Project description:Hepatocytes isolated from DILI patient's liver (#2064) were cultured for a long term using irrMEF and EMUKK-05, and comprehensive gene expression was compared between Puromycin-treated and non-treated groups. In addition, comprehensive gene expression analysis of human mature hepatocytes, primary cultured cells, and ips cell-derived hepatocyte-like cells were performed as controls. Two-condition experiment, Proliferating hepatocytes (ProilHH) vs. puromycin-treated ProliHH. Primary human hepatocytes (PHH) and isolated humen mature hepatocytes (MH) and human iPSC-derived hepatocyte-like cells (HLC) as controls.

2021-12-30 | GSE192653 | GEO

Reprogramming of prostate cancer-associated stromal cells

Project description:CD90+ prostate cancer-associated (CP) stromal cells represent a disease cell type found only in tumor tissue. Genetic reprogramming by induced pluripotent stem (iPS) cell technology might be used to “normal gene expression of diseased cells thereby providing a cure. The resultant iPS cells would no longer express the disease program, and, like stem cells, might respond to normal differentiative signaling. Thus, CP stromal cells, isolated from tumor tissue and cultured in vitro, were transfected with POU5F1/LIN28/NANOG/SOX2 lentiviral vectors. iPS cells were obtained at a frequency of 10^4. Transcriptome analysis showed an almost complete match in gene expression between the iPS cells and human embryonic stem cells. Genes of CP stromal cells were fully inactivated.

2012-01-28 | GSE35373 | GEO

Reprogramming of prostate cancer-associated stromal cells

2012-01-28 | E-GEOD-35373 | biostudies-arrayexpress

Omics analyses of 3T3-J2 feeder cells to identify culture conditions that support the long-term culture of human pancreatic progenitor cells

Project description:Multipotent pancreatic progenitor cells have been successfully cultured, expanded and differentiated into cells of the adult human pancreas. The long-term culture of these progenitors (termed cPP) relies on support from mitotically inactivated 3T3-J2 mouse embryonic fibroblasts. The 3T3-J2-derived signals that support cPP expansion and maintain the fine balance between self-renewal and lineage commitment in this co-culture system remain unknown. To unmask these signals, we exploited a striking disparity in morphology and the capacity to self-renew of cPP cultured on 3T3-J2 cells from different sources. We deployed a comparative approach to identify (1) genes that define expandable cPP through transcriptome analysis and (2) key factors secreted by 3T3-J2 using selective enrichment of newly synthesised proteins and mass spectrometry analysis. Using cPP from three genetic backgrounds cultured on either supportive or non-supportive 3T3-J2, these analyses revealed 100 transcription factor genes that are significantly down-regulated in cPP cultured on non-supportive 3T3-J2. Analysis of differentially expressed 3T3-J2 proteins identified 53 whose expression is higher in supportive 3T3-J2. These results provide significant insight into the requirements not only for optimal cPP culture and expansion but also for progenitor cell types in other organ systems that rely on 3T3-J2 co-culture, most notably keratinocytes for clinical applications.

2024-04-24 | PXD041758 | JPOST Repository

GENERATION OF HEPATIC STELLATE CELLS BY DIRECTED DIFFERENTIATION OF HUMAN PLURIPOTENT STEM CELLS

Project description:Hepatic stellate cells (HSC) are the main stromal cell component of the liver. In healthy liver, quiescent HSC participate in the homeostasis of extracellular matrix (ECM) and store vitamin A. Liver injury causes HSC activation, where they participate in the wound-healing response, by producing ECM components as well as cytokines involved in liver regeneration and inflammation. Moreover, HSC are the main cell type responsible for fibrosis progression. The lack of homogeneous cultures and renewable sources of human HSC has limited the studies of the role of HSC in liver injury, repair anf fibrosis. Here we report a procedure to direct the differentiation of human pluripotent stem cells (PSC) to HSC. The HSC–like population (iPS-HSC) was enriched in PDGFRβ positive cells that expressed key HSC markers. Whole genome transcriptomic analysis revealed that iPS-HSC displayed features intermediate to quiescent and activated HSC. Functional analysis demonstrated that iPS-HSC accumulated retinyl esters into lipid droplets and responded to injury mediators. Moreover, when cultured with HepaRG hepatocytes as aggregates, iPS-HSC support long-term hepatocyte metabolic function and respond to hepatocyte toxicity by activating and promoting organoid fibrogenesis.

2018-06-28 | GSE90525 | GEO

Expression data of hepatocytes isolated from chimeric mouse livers repopulated with human hepatocytes and from normal human livers

Project description:We generated chimeric mice with livers that were predominantly repopulated with human hepatocytes. Hepatocytes were isolated from the chimeric mouse livers and their gene expressions were compared with hepatocytes isolated from normal human livers . Cluster and principal components analyses showed that gene expression profiles of hepatocytes from the chimeric mice and those from normal human livers were extremely closed. Additionally, we performed microarray experiments to examine gene expression in human tissues. This data was used for comparison with hepatocytes. A total of 22 tissues (bone marrow, cerebellum, colon, cortex, fetal brain, heart, kidney, liver, lung, pancreas, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea and uterus) were examined. The chimeric mice were generated by transplantation of 2 different donor hepatocytes. Hepatocytes were isolated from the mouse livers and normal human livers, and their cDNAs were used for microarray analysis. Total RNA isolated from human tissues and cell cultures were labeled and hybridized to the GeneChip Human Genome U133 Plus 2.0 Array according to the manufacturer's protocol.

2012-11-27 | E-GEOD-33846 | biostudies-arrayexpress

RNA-Seq Analysis Reveals Different Dynamics of Differentiation of Human Dermis- and Adipose-derived Stromal Stem Cells

Project description:Background: Tissue regeneration and recovery in the adult body depends on self-renewal and differentiation of stem and progenitor cells. Mesenchymal stem cells (MSCs) that have the ability to differentiate into various cell types, have been isolated from the stromal fraction of virtually all tissues. However, little is known about the true identity of MSCs. MSC populations exhibit great tissue-, location- and patient-specific variation in gene expression and are heterogeneous in cell composition. Methodology/Principal findings: Our aim was to analyze the dynamics of differentiation of two closely related stromal cell types, adipose tissue-derived MSCs and dermal fibroblasts (FBs) along adipogenic, osteogenic and chondrogenic lineages using multiplex RNA-seq technology. We found that undifferentiated donor-matched MSCs and FBs are distinct populations that stay different upon differentiation into adipocytes, osteoblasts and chondrocytes. The changes in lineage-specific gene expression occur early in differentiation and persist over time in both MSCs and FBs. Further, MSCs and FBs exhibit similar dynamics of adipogenic and osteogenic differentiation but different dynamics of chondrogenic differentiation. Conclusion: Our findings suggest that stromal stem cells including adipose-derived MSCs and dermal FBs exploit different molecular mechanisms of differentiation to reach a common cell fate. The early mechanisms of differentiation are lineage-specific and are similar for adipogenic and osteogenic differentiation but are distinct for chondrogenic differentiation between MSCs and FBs. A total of 91 samples were analyzed by multiplex RNA-seq. Samples represented replicates from two patients, two cell types and three differentiation protocols, as indicated by the sample annotation. 5 barcodes were unused, but the corresponding FASTQ files are included for completeness.

2012-06-27 | E-GEOD-37521 | biostudies-arrayexpress

Defining the Tumor Microenvironment by Integration of Im-munohistochemistry and Extracellular Matrix Targeted Imaging Mass Spectrometry

Project description:Breast stroma plays a significant role in breast cancer risk and progression yet remains poorly understood. In breast stroma, collagen is the most abundantly expressed protein and its increased deposition and alignment contributes to progression and poor prognosis. Collagen post-translation modifications such as hydroxylated-proline (HYP) control deposition and stromal organization. The clinical relevance of collagen HYP site modifications in cancer processes remains undefined due to technical issues accessing collagen from formalin-fixed, paraffin-embedded (FFPE) tissues. We previously developed a targeted approach for investigating collagen and other extracellular matrix proteins from FFPE tissue. Here, we hypothesized that immunohistochem-istry staining for fibroblastic markers would not interfere with targeted detection of collagen stroma peptides and could reveal peptide regulation influenced by specific cell types. Our initial work demonstrated that stromal peptide peak intensities when using MALD-IMS following IHC staining (αSMA, FAP, P4HA3 and PTEN) were comparable to serial sections of non-stained tissue. Analysis of histology-directed IMS using PTEN on breast tissues and TMAs revealed heteroge-neous PTEN staining patterns and suggestive roles in stromal protein regulation. This study sets the foundation for investigations of target cell types and their unique contribution to collagen regulation within extracellular matrix niches.

2022-02-15 | PXD028107 | Pride

Large-scale secretome analyses unveil a superior immunosuppressive phenotype from umbilical cord stromal cells compared to other adult mesenchymal stromal cells

Project description:Mesenchymal stromal cells (MSCs) with regenerative and immunomodulatory potential are being investigated as a potential therapeutic tool for cartilage lesions. MSCs express a wide variety of bioactive molecules including cytokines, trophic factors, and proteases, which act in a paracrine fashion to modulate the tissue microenvironment. Yet, little is known about the divergence of these signalling molecules between MSCs populations from adult or young tissues. This makes it challenging to decide the optimal source of MSCs for a specific clinical application. In this study, we investigated cell secretomes from cultured human stromal cells harvested from Hoffa’s fat pad (HFPSCs), synovial membrane (SMSCs), umbilical cord (UCSCs) and cartilage (ACs) by quantitative LC-MS/MS proteomics. We also performed multiplex protein arrays and functional assays to compare the constitutive immunomodulatory capabilities of different MSCs. Proteins involved in extracellular matrix degradation and inflammation such as MMPs, IL-17, and complement factors were significantly downregulated in UCSCs compared to other cell types. Additionally, we found enhanced expression of TGF-β1 and PGE2 in UCSCs supernatants. UCSCs were superior in inhibiting peripheral blood mononuclear cells proliferation, migration and TNF-α and IFN-γ secretion compared to ACs, HFPSCs and SMSCs. Although all cell types could repress HLA-DR surface expression and cytokine release by activated macrophages, only UCSCs significantly blocked IL-6 and IL-12 production. Our data demonstrate that stromal cells from umbilical cords display superior anti-inflammatory and immunosuppressive properties than stromal cells from adult tissues. This Allogeneic cell source could potentially be considered as an adjuvant therapy for articular cartilage repair.

2019-01-29 | PXD011762 | Pride

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