Mechano-modulatory synthetic niches for liver organoid derivation

Sorrentino, Giovanni; Rezakhani, Saba; Yildiz, Ece; Nuciforo, Sandro; Heim, Markus H.

doi:10.1101/810275

Cited by 9 publications

(16 citation statements)

References 43 publications

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“…Additionally, ECM components proven to be advantageous for organoid growth, such as laminin-111, collagen IV, and fibronectin, could be incorporated. [32] Morphological appearance and metabolic activity results of the human liver organoids in MG in EM and DM conditions are consistent with previously shown results. [9] The morphology of the organoids in CNF hydrogel appear darker, not as round and with a less even surface as compared MG cultures.…”

Section: Human Liver Organoid Performancesupporting

confidence: 89%

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Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Krüger

Oosterhoff

Wolferen

et al. 2020

Adv Healthcare Materials

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To replicate functional liver tissue in vitro for drug testing or transplantation, 3D tissue engineering requires representative cell models as well as scaffolds that not only promote tissue production but also are applicable in a clinical setting. Recently, adult liver‐derived liver organoids are found to be of much interest due to their genetic stability, expansion potential, and ability to differentiate toward a hepatocyte‐like fate. The current standard for culturing these organoids is a basement membrane hydrogel like Matrigel (MG), which is derived from murine tumor material and apart from its variability and high costs, possesses an undefined composition and is therefore not clinically applicable. Here, a cellulose nanofibril (CNF) hydrogel is investigated with regard to its potential to serve as an alternative clinical grade scaffold to differentiate liver organoids. The results show that its mechanical properties are suitable for differentiation with overall, either equal or improved, functionality of the hepatocyte‐like cells compared to MG. Therefore, and because of its defined and tunable chemical definition, the CNF hydrogel presents a viable alternative to MG for liver tissue engineering with the option for clinical use.

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Section: Human Liver Organoid Performancesupporting

confidence: 89%

“…Additionally, ECM components proven to be advantageous for organoid growth, such as laminin‐111, collagen IV, and fibronectin, could be incorporated. [ 32 ]…”

Section: Discussionmentioning

confidence: 99%

Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Krüger

Oosterhoff

Wolferen

et al. 2020

Adv Healthcare Materials

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“…These organoid culture matrices were functionalized with adhesion peptides, in some cases also laminin‐111, [ 9 ] and were formulated at an optimal shear modulus ( G ′) of ≈1.3 kPa. [ 9,10 ] These enzymatically crosslinked PEG matrices have served as an important starting point to define the key requirements for epithelial stem cell expansion, tissue growth, and subsequent organoid development, revealing for example an important role of gel stiffness in controlling multiple steps of in vitro organogenesis. However, the complexity of the hydrogel crosslinking chemistry, as well as high costs and batch‐to‐batch variability associated with the crosslinking enzyme FXIIIa, arguably limits its broader applicability.…”

Section: Introductionmentioning

confidence: 99%

Low‐Defect Thiol‐Michael Addition Hydrogels as Matrigel Substitutes for Epithelial Organoid Derivation

Rezakhani

Gjorevski

2020

Adv Funct Materials

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Due to their selective crosslinking chemistry and well-defined mechanobiochemical characteristics, hydrogels crosslinked by thiol-Michael addition reactions have garnered immense interest for 3D cell culture applications. These hydrogels are typically formed via end-linking of bis-cysteine oligopeptides and branched f-functional (f ≥ 3) poly(ethylene glycol) (PEG). Unfortunately, this gel design accumulates excessive structural defects at a solid content below ≈10% (w/v) due to diluted bifunctional components reacting intramolecularly to form primary loops that compromise the gels' mechanical integrity and lead to excessive swelling. These limitations restrict the suitability of the gels for challenging cell culture applications, such as the growth of organoids. Here, low-defect thiol-Michael addition (LDTM) hydrogels based on novel building blocks designed toward minimizing structural defects are reported. Compared to the conventional gels, LDTM gels can be generated at an at least 2-fold lower solid content, while still incorporating high concentrations of bioactive ligands (≈3 × 10-3 m). LDTM gels promote the efficient development of fully patterned mouse intestinal organoids as well as human intestinal organoids, the latter in the absence of any animal-derived components. Powerful alternatives are thus provided to the gold-standard Matrigel, which is expensive and too variable for robust organoid development, facilitating translational applications of organoids.

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“…However, disadvantages of animal derived hydrogels include lot‐to‐lot variability, an incompletely defined matrix, and species differences which limit applications for translational and in vivo use. Recent progress has systematically developed chemically defined synthetic hydrogels to culture stem cell derived human intestinal and liver organoids that result in organoids that are comparable to those embedded in Matrigel and in some cases can be frozen and thawed (Gjorevski et al., 2016; Kruger et al., 2020; Sorrentino et al., 2020). This new work opens customizable possibilities for clinically relevant studies necessitating defined materials.…”

Section: Ecm Variations/synthetic Scaffolds/specialized Platesmentioning

confidence: 99%

Human liver model systems in a dish

Thompson

Takebe

2021

Dev Growth Differ

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The human adult liver has a multi‐cellular structure consisting of large lobes subdivided into lobules containing portal triads and hepatic cords lined by specialized blood vessels. Vital hepatic functions include filtering blood, metabolizing drugs, and production of bile and blood plasma proteins like albumin, among many other functions, which are generally dependent on the location or zone in which the hepatocyte resides in the liver. Due to the liver's intricate structure, there are many challenges to design differentiation protocols to generate more mature functional hepatocytes from human stem cells and maintain the long‐term viability and functionality of primary hepatocytes. To this end, recent advancements in three‐dimensional (3D) stem cell culture have accelerated the generation of a human miniature liver system, also known as liver organoids, with polarized epithelial cells, supportive cell types and extra‐cellular matrix deposition by translating knowledge gained in studies of animal organogenesis and regeneration. To facilitate the efforts to study human development and disease using in vitro hepatic models, a thorough understanding of state‐of‐art protocols and underlying rationales is essential. Here, we review rapidly evolving 3D liver models, mainly focusing on organoid models differentiated from human cells.

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Mechano-modulatory synthetic niches for liver organoid derivation

Cited by 9 publications

References 43 publications

Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Cellulose Nanofibril Hydrogel Promotes Hepatic Differentiation of Human Liver Organoids

Low‐Defect Thiol‐Michael Addition Hydrogels as Matrigel Substitutes for Epithelial Organoid Derivation

Human liver model systems in a dish

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