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Curated Papers > In recent years, high-impact research on "organoids" (IF≥30, last 5 years)

Geometric engineering of organoid culture for enhanced organogenesis in a dish. ​

Literature Information ​

DOI10.1038/s41592-022-01643-8
PMID36280722
JournalNature methods
Impact Factor32.1
JCR QuartileQ1
Publication Year2022
Times Cited27
Keywordsorganoid culture, stem cell suspension, inflammatory bowel disease, single-cell RNA sequencing, vascularization
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't
ISSN1548-7091
Pages1449-1460
Issue19(11)
AuthorsSunghee Estelle Park, Shawn Kang, Jungwook Paek, Andrei Georgescu, Jeehan Chang, Alex Yoon Yi, Benjamin J Wilkins, Tatiana A Karakasheva, Kathryn E Hamilton, Dan Dongeun Huh

TL;DR ​

This study presents a novel and scalable method for the long-term culture and maturation of organoids, enabling the creation of radial arrays from stem cell suspensions without passaging, which enhances the structural and functional maturity of intestinal organoids over four weeks. Additionally, the researchers developed a patient-derived organoid model of inflammatory bowel disease (IBD) that accurately replicates IBD features, paving the way for advanced modeling of organ-like structures and immune responses in vitro.

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organoid culture · stem cell suspension · inflammatory bowel disease · single-cell RNA sequencing · vascularization

Abstract ​

Here, we introduce a facile, scalable engineering approach to enable long-term development and maturation of organoids. We have redesigned the configuration of conventional organoid culture to develop a platform that converts single injections of stem cell suspensions to radial arrays of organoids that can be maintained for extended periods without the need for passaging. Using this system, we demonstrate accelerated production of intestinal organoids with significantly enhanced structural and functional maturity, and their continuous development for over 4 weeks. Furthermore, we present a patient-derived organoid model of inflammatory bowel disease (IBD) and its interrogation using single-cell RNA sequencing to demonstrate its ability to reproduce key pathological features of IBD. Finally, we describe the extension of our approach to engineer vascularized, perfusable human enteroids, which can be used to model innate immune responses in IBD. This work provides an immediately deployable platform technology toward engineering more realistic organ-like structures in a dish.

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Primary Questions Addressed ​

  1. What are the specific advantages of using radial arrays of organoids over traditional organoid culture methods?
  2. How does the engineering approach impact the scalability of organoid production for clinical applications?
  3. In what ways can the patient-derived organoid model of inflammatory bowel disease be further utilized for drug testing or personalized medicine?
  4. What are the potential challenges in maintaining the structural and functional maturity of organoids over extended periods?
  5. How can the engineered vascularized, perfusable human enteroids contribute to our understanding of other diseases beyond inflammatory bowel disease?

Key Findings ​

Research Background and Objectives ​

The study addresses the challenges associated with the long-term culture and maturation of organoids, which are miniaturized and simplified versions of organs. Traditional organoid culture methods often require frequent passaging and do not support sustained growth and functional maturity. The primary objective of this research is to develop a scalable engineering approach that allows for the extended development of organoids from stem cell suspensions without the need for passaging.

Main Methods/Materials/Experimental Design ​

The authors redesigned the conventional organoid culture system, introducing a platform that enables the transformation of single injections of stem cell suspensions into radial arrays of organoids. The key components of the methodology are as follows:

  • Stem Cell Injection: A single injection of stem cell suspensions into the culture system.
  • Radial Array Formation: The engineered platform facilitates the organization of organoids into radial arrays.
  • Extended Culture: Organoids are maintained in this configuration for over 4 weeks, allowing for continuous development and maturation.

The following flowchart illustrates the technical approach:

Mermaid diagram

Key Results and Findings ​

  1. Enhanced Maturity: The newly developed platform resulted in the accelerated production of intestinal organoids that exhibit significantly improved structural and functional maturity.
  2. Inflammatory Bowel Disease Model: The patient-derived organoid model effectively reproduced key pathological features of inflammatory bowel disease (IBD), confirmed through single-cell RNA sequencing.
  3. Vascularized Organoids: The approach was successfully extended to create vascularized, perfusable human enteroids, which can be utilized to study innate immune responses in IBD.

Main Conclusions/Significance/Innovation ​

The research presents a novel, scalable technology for engineering organoids that can be maintained long-term without passaging. This advancement is significant as it allows for the creation of more realistic organ-like structures in vitro, facilitating better modeling of human diseases such as IBD. The integration of single-cell RNA sequencing provides deeper insights into the cellular mechanisms underlying these diseases. This work opens avenues for further research and applications in regenerative medicine and disease modeling.

Research Limitations and Future Directions ​

Limitations:

  • The study primarily focuses on intestinal organoids and IBD, which may limit the generalizability of the findings to other organ systems.
  • Long-term viability and functionality beyond 4 weeks were not extensively tested.

Future Directions:

  • Expansion of the platform to other types of organoids, including those from different tissues.
  • Investigating the long-term culture potential and functionality of these organoids beyond the initial timeframe.
  • Exploring the use of this technology in drug testing and personalized medicine applications.
AspectDetails
Research FocusLong-term organoid culture and maturation
Key InnovationsRadial array formation, patient-derived models
Model SystemsIntestinal organoids, vascularized human enteroids
ApplicationsDisease modeling, regenerative medicine
Future Research AreasOther organ types, extended functionality testing

References ​

  1. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. - Lance W Peterson;David Artis - Nature reviews. Immunology (2014)
  2. Molecular mechanisms of calcium signaling in the modulation of small intestinal ion transports and bicarbonate secretion. - Xin Yang;Guorong Wen;Biguang Tuo;Fenglian Zhang;Hanxing Wan;Jialin He;Shiming Yang;Hui Dong - Oncotarget (2018)
  3. Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche. - Yuli Wang;Raehyun Kim;Samuel S Hinman;Bailey Zwarycz;Scott T Magness;Nancy L Allbritton - Cellular and molecular gastroenterology and hepatology (2018)
  4. Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine. - Yalong Wang;Wanlu Song;Jilian Wang;Ting Wang;Xiaochen Xiong;Zhen Qi;Wei Fu;Xuerui Yang;Ye-Guang Chen - The Journal of experimental medicine (2020)
  5. Paneth Cells Respond to Inflammation and Contribute to Tissue Regeneration by Acquiring Stem-like Features through SCF/c-Kit Signaling. - Mark Schmitt;Matthias Schewe;Andrea Sacchetti;Danny Feijtel;Wesley S van de Geer;Miriam Teeuwssen;Hein F Sleddens;Rosalie Joosten;Martin E van Royen;Harmen J G van de Werken;Johan van Es;Hans Clevers;Riccardo Fodde - Cell reports (2018)
  6. Development-on-chip: in vitro neural tube patterning with a microfluidic device. - Christopher J Demers;Prabakaran Soundararajan;Phaneendra Chennampally;Gregory A Cox;James Briscoe;Scott D Collins;Rosemary L Smith - Development (Cambridge, England) (2016)
  7. Cytoskeletal Organization and Cell Polarity in the Pathogenesis of Crohn's Disease. - Chengcen Guo;Jun Shen - Clinical reviews in allergy & immunology (2021)
  8. A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids. - Briana R Dye;Priya H Dedhia;Alyssa J Miller;Melinda S Nagy;Eric S White;Lonnie D Shea;Jason R Spence - eLife (2016)
  9. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. - Toshiro Sato;Hans Clevers - Science (New York, N.Y.) (2013)
  10. Organoid-based modeling of intestinal development, regeneration, and repair. - Joep Sprangers;Irene C Zaalberg;Madelon M Maurice - Cell death and differentiation (2021)

Literatures Citing This Work ​

  1. Suspended hydrogel culture as a method to scale up intestinal organoids. - Julia Y Co;Jessica A Klein;Serah Kang;Kimberly A Homan - Scientific reports (2023)
  2. Exploring New Dimensions of Tumor Heterogeneity: The Application of Single Cell Analysis to Organoid-Based 3D In Vitro Models. - Natalie Landon-Brace;Nancy T Li;Alison P McGuigan - Advanced healthcare materials (2023)
  3. Fibrin Stiffness Regulates Phenotypic Plasticity of Metastatic Breast Cancer Cells. - Maria Heilala;Arttu Lehtonen;Ossi Arasalo;Aino Peura;Juho Pokki;Olli Ikkala; Nonappa;Juha Klefström;Pauliina M Munne - Advanced healthcare materials (2023)
  4. Setting standards for stem cells. - Nature methods (2023)
  5. Articular cartilage repair biomaterials: strategies and applications. - Mingkai Wang;Yan Wu;Guangfeng Li;Qiushui Lin;Wencai Zhang;Han Liu;Jiacan Su - Materials today. Bio (2024)
  6. Breast organoid suspension cultures maintain long-term estrogen receptor expression and responsiveness. - Joan Brugge;Kung-Chi Chang;Francesca Silvestri;Michael Olipant;M Angie Martinez-Gakidis;Dennis Orgill;Judy Garber;Deborah Dillon - Research square (2024)
  7. Optimization of Vascularized Intestinal Organoid Model. - Zhang Wen;Mariabelen Orduno;Zixie Liang;Xiangyu Gong;Michael Mak - Advanced healthcare materials (2024)
  8. Pharmacological Approaches to Hearing Loss. - Christopher R Cederroth;Jonas Dyhrfjeld-Johnsen;Barbara Canlon - Pharmacological reviews (2024)
  9. Intestinal organ chips for disease modelling and personalized medicine. - Alican Özkan;Nina Teresa LoGrande;Jessica F Feitor;Girija Goyal;Donald E Ingber - Nature reviews. Gastroenterology & hepatology (2024)
  10. Scalable production of uniform and mature organoids in a 3D geometrically-engineered permeable membrane. - Dohui Kim;Hyeonji Lim;Jaeseung Youn;Tae-Eun Park;Dong Sung Kim - Nature communications (2024)

... (17 more literatures)

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