Tissue extracellular matrix hydrogels as alternative to Matrigel for culturing gastrointestinal organoids
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ABSTRACT:
PROVIDER: PRJNA694052 | ENA |
REPOSITORIES: ENA
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Project description:Matrigel, a mouse tumor extracellular matrix (ECM) protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and regenerative medicine due to its tumor-derived origin, batch-to batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal (GI) tissue-derived ECM hydrogels are a suitable substitute for Matrigel in GI organoid culture. We found that the development and function of GI organoids grown in GI ECM hydrogels are comparable or often superior to those in Matrigel. In addition, GI ECM hydrogels enabled long-term subculture and transplantation of GI organoids by providing GI tissue-mimetic microenvironments. Tissue-specific and age-related ECM profiles of GI ECM hydrogels that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that ECM hydrogels derived from decellularized GI tissues are an effective alternative to the current gold standard, Matrigel, and produce organoids suitable for GI disease modeling, drug development, and tissue regeneration.
2022-02-10 | PXD023694 | Pride
Project description:Matrigel, a mouse tumor extracellular matrix (ECM) protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and regenerative medicine due to its tumor-derived origin, batch-to22 batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal (GI) tissue-derived ECM hydrogels are a suitable substitute for Matrigel in GI organoid culture. We found that the development and function of GI organoids grown in GI ECM hydrogels are comparable or often superior to those in Matrigel. In addition, GI ECM hydrogels enabled long-term subculture and transplantation of GI organoids by providing GI tissue-mimetic microenvironments. Tissue-specific and age-related ECM profiles of GI ECM hydrogels that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that ECM hydrogels derived from decellularized GI tissues are an effective alternative to the current gold standard, Matrigel, and produce organoids suitable for GI disease modeling, drug development, and tissue regeneration.
2022-01-31 | PXD023705 | Pride
Project description:To determine the performance of the decellularized GI tissue ECM hydrogel, we analyzed differences in mRNA expression levels in native gastric tissues, gastric organoids cultured in Matrigel and those cultured in decellularized gastric ECM hydrogel. We also compared mRNA expression levels of native small intestinal tissues, small intestinal organoids grown in Matrigel and those grown in decellularized intestinal ECM hydrogel.
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Project description:scRNA-seq was used to characterise hiPSC-derived kidney organoids differentiated within fully synthetic self-assembling peptide hydrogels of variable mechanical strengths and compare these to organoids differentiated within the animal-derived matrix, Matrigel. Organoids were matured in the respective matrices until day 24 of differentiation and 6 organoids per support matrix were then pooled and dissociated using the cold-active protease from Bacillus licheniformis. Cells were processed on the 10x Genomics Chromium platform using the Single-Cell 3’ v3.1 protocol. The NextSeq500 (Illumina) was used to sequence the libraries generated and initial processing of the data was carried out using the 10X Genomic Cell Ranger v3.1.0 pipeline.
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Project description:Organoid technology has provided unique insights into human organ development, function, and diseases. Patient derived organoids are increasingly used for drug screening, modeling rare disorders, designing regenerative therapies, and understanding pathological changes associated with disease progression. However, the use of Matrigel to grow organoids represents a major challenge in the clinical translation of organoid technology. Matrigel is a poorly defined cocktail of extracellular matrix proteins and growth factors extracted from the Engelbreth Holm Swarm mouse tumor. The extracellular matrix is a major driver of multiple cellular processes and differs significantly between tissues as well as in healthy and diseases states of the same tissue. Therefore, we envisioned that extracellular matrix derived from a native healthy tissue would be sufficient to support organoid growth akin to organogenesis in vivo. Here, we have developed hydrogels from decellularized human and bovine endometrium. These hydrogels supported the growth of mouse and human endometrial organoids, which was comparable to Matrigel. Organoids grown in endometrial hydrogels were proteomically more similar to the native tissue than the organoids cultured in Matrigel. Proteomic and Raman spectroscopy analyses showed that the method of decellularization affects the biochemical composition of hydrogels and subsequently, their ability to support organoid growth. The amount of laminin in hydrogels correlated with the number and the shape of organoids. We also demonstrated the utility of endometrial hydrogels in developing solid scaffolds for supporting high throughput cell culture-based applications. In summary, endometrial hydrogels overcome a major limitation of organoid technology and greatly expand the applicability of organoids to understand endometrial biology and associated pathologies.
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Project description:Biologically ligands (e.g., RGDS from fibronectin: Fn-RGD) play a critical role in the development of chemically defined biomaterials. However, there has been limited progress in recent decades towards discovering novel extracellular-matrix-protein-derived ligands for translational applications. Here, by combining motif analysis of evolutionarily conserved RGD-containing regions in laminin (Ln) with functional microarray screening, we identified a Ln-derived angiogenic peptide (LDAP) that showed enhanced proangiogenic activities over commonly used Fn-RGD. Mechanistic studies using RNA-sequencing of LDAP functionalized hydrogels showed an improved angiogenic transcriptome over Fn-RGD functionalized hydrogels and high similarity to Matrigel, attributed to the ability of LDAP to engage both Ln- and Fn-binding integrins. Injectable hydrogels functionalized with LDAP, along with MMP-QK (a VEGF-mimetic peptide), exhibited increased functional recovery over decellularized extracellular matrix (dECM) and alginates functionalized with Fn-RGD and MMP-QK in a mouse ischemic hindlimb model, illustrating the power of the strategy to rapidly develop potent chemically-defined biomaterials for therapeutic applications.
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Project description:We report that differentiation of the C2C12 myoblast line on patterened hydrogels results in the increased expression of muscle sarcomere genes and more closely models expression changes that happen in in vivo muscle differentiation than do C2C12 myoblasts cultured on unpatterened substrates.
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Project description:Remodeling and increased stiffness of the extracellular matrix is a hallmark of solid cancers and contributes to tumor progression through increased proliferation, survival and migration. Mechanotransduction, the process in which cells sense and transduce mechanical signals, can result in transcriptional changes that in turn alter cellular behavior. In vitro culturing of MCF10ACA1a (CA1a) breast cancer cells on polyacrylamide-based hydrogels of variable stiffness revealed drastic changes in morphology, indicating a stiffness dependent induction of a malignant phenotype. We used DNA microarray to characterize the transcriptome of CA1a cells on low (400 Pa) and high (5000 Pa) stiffness, corresponding to the stiffness of normal breast and breast cancer, respectively.
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Project description:Alveolar type 2 epithelial cells (AT2s) derived from human induced pluripotent stem cells (iAT2s) have rapidly contributed to our understanding of AT2 function and disease. However, as iAT2s are primarily cultured in three-dimensional (3D) Matrigel, a matrix derived from cancerous mouse tissue, it is unclear the impact a physiologically relevant matrix will have on iAT2s. Herein, we derive hydrogels from decellularized human lung alveolar-enriched extracellular matrix (aECM) to provide a relevant ex vivo model for the 3D culture of iAT2s. We demonstrate aECM hydrogels retain critical in situ ECM components, including structural and basement membrane proteins. While aECM hydrogels facilitate iAT2 proliferation and alveolosphere formation, a subset of iAT2s rapidly change morphology to thin and elongated ring-like cells. This morphological change correlates with upregulation of recently described iAT2-derived transitional cell state genetic markers. As such, we demonstrate a potentially underappreciated role of physiologically relevant aECM in iAT2 differentiation.
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