The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
PEG-4MAL hydrogels for human organoid generation, culture, and in vivo delivery
Open accessAbstract
In vitro differentiation of human pluripotent stem cell (hPSC)-derived organoids (HOs) facilitates the production of multicellular three-dimensional structures analogous to native human tissues. Most current methods for the generation of HOs rely on Matrigel, a poorly defined basement membrane derivative secreted by Engelbreth-Holm-Swarm mouse sarcoma cells, limiting the potential use of HOs for regenerative medicine applications. Here, we describe a protocol for the synthesis of a fully defined, synthetic hydrogel that supports the generation and culture of HOs. Modular, cell-encapsulating hydrogels are formed from a four-armed poly(ethylene glycol) macromer that has maleimide groups at each terminus (PEG-4MAL) and is conjugated to cysteine-containing adhesive peptides and cross-linked via protease-degradable peptides. The protocol also includes guidelines for the localized in vivo delivery of PEG-4MAL hydrogel-encapsulated HOs to injured mouse colon. The PEG-4MAL hydrogel supports the engraftment of the HOs and accelerates colonic wound repair. This culture and delivery strategy can thus be used to develop HO-based therapies to treat injury and disease. Hydrogel and tissue preparation and subsequent encapsulation can be performed within 2.5-3.5 h. Once HOs have been cultured in synthetic hydrogels for at least 14 d, they can be prepared and delivered to the mouse colon in under 5 h.
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“Intriguingly, when PEG was crosslinked with dithiothreitol to inhibit matrix degradation, organoid viability at seven days was poor as measured by live-dead staining.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [164]
In the citing paper
“Organoid viability was reduced at high PEG density and matrix stiffness;”
From Towards organoid culture without Matrigel (2021) · cites this paper as [164]
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“RGD- or AG73 (CGGRKRLQVQLSIRT)-functionalized PEG matrices promoted greater organoid viability than laminin-derived IKVAV- or type I collagen-derived GFOGER peptides163,164.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [164]
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“Cruz-Acuna and colleagues also found that PEG-based materials may need to be soft and degradable in order to support differentiated intestinal organoids.”
From Towards organoid culture without Matrigel (2021) · cites this paper as [164]
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Cites
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Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro
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Self-citationGeneration of cerebral organoids from human pluripotent stem cells
Lancaster, M. A., & Knoblich, J. A. (2014) · Nature Protocols · doi:10.1038/nprot.2014.158 · Cited by 1,823
Matrigel: A complex protein mixture required for optimal growth of cell culture
Hughes, C. S., Postovit, L. M., & Lajoie, G. A. (2010) · PROTEOMICS · doi:10.1002/pmic.200900758 · Cited by 1,534
Organoids as an in vitro model of human development and disease
Fatehullah, A., Tan, S. H., & Barker, N. (2016) · Nature Cell Biology · doi:10.1038/ncb3312 · Cited by 1,508
Bioactive modification of poly (ethylene glycol) hydrogels for tissue engineering
Zhu, J. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.02.044 · Cited by 1,457
Self-formation of optic cups and storable stratified neural retina from human ESCs
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Designer matrices for intestinal stem cell and organoid culture
Gjorevski, N., Sachs, N., Manfrin, A., Giger, S., Bragina, M. E., Ordóñez-Morán, P., Clevers, H., & Lutolf, M. P. (2016) · Nature · doi:10.1038/nature20168 · Cited by 1,426
Cited by
Sorted by citations
Human organoids: model systems for human biology and medicine
Kim, J., Koo, B.-K., & Knoblich, J. A. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0259-3 · Cited by 2,187
Synthetic alternatives to Matrigel
Aisenbrey, E. A., & Murphy, W. L. (2020) · Nature Reviews Materials · doi:10.1038/s41578-020-0199-8 · Cited by 1,016
Nicolas, J., Magli, S., Rabbachin, L., Sampaolesi, S., Nicotra, F., & Russo, L. (2020) · Biomacromolecules · doi:10.1021/acs.biomac.0c00045 · Cited by 509
Towards organoid culture without Matrigel
Kozlowski, M. T., Crook, C. J., & Ku, H. T. (2021) · Communications Biology · doi:10.1038/s42003-021-02910-8 · Cited by 409
Nonadhesive Alginate Hydrogels Support Growth of Pluripotent Stem Cell-Derived Intestinal Organoids
Capeling, M. M., Czerwinski, M., Huang, S., Tsai, Y.-H., Wu, A., Nagy, M. S., Juliar, B., Sundaram, N., Song, Y., Han, W. M., et al. (2019) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.12.001 · Cited by 226
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Metadata
- Authors
- Cruz-Acuña, R., Quirós, M., Huang, S., Siuda, D., Spence, J. R., Nusrat, A., & García, A. J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Spence, Jason R.
- Nusrat, Asma
- Venue
- Nature Protocols
- Published
- 2018-09
- Volume
- 13
- Issue
- 9
- Pages
- 2102-2119
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- PMC
- PMC7240347
- OpenAlex
- W2892378739
- Cited by
- 168
- References
- 30
- Citations by year
- 2026: 16 · 2025: 26 · 2024: 16 · 2023: 24 · 2022: 26 · 2021: 30 · 2020: 16 · 2019: 14
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-10-24)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000454)
- National Heart, Lung, and Blood Institute (R01HL119215)
- National Institute of Allergy and Infectious Diseases (U19AI116482)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK085532, P30DK034933, R01DK055679, R56DK089763, R29DK055679, R01DK059888, U01DK085532, U01DK103141, R01DK089763)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062368, R01AR062920)
- National Center for Advancing Translational Sciences
- Topics
- Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- human organoids, pluripotent stem cell differentiation, synthetic hydrogels, hydrogel encapsulation, in vivo delivery, tissue regeneration
- MeSH terms
- Animals, Colon, Humans, Organoids, Organ Transplantation, Hydrogels, Models, Animal, Pluripotent Stem Cells, Tissue Culture Techniques, Mice
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