The Gastric Organoids

  • Challenges in research on human stomach and gastric cancer
  • Opportunities on organoid technology in scientific research
  • Application of gastric organoids in research
  • Scientists make gastric organoids with smooth muscle contraction
  • Using gastric epithelium organoids with the CRISPR technology to provide insights on biological phenomena
  • Example on limitation of current gastric organoid technology
  • Some future trends on gastric organoid technology
  • Selected compositions for gastric organoid culture recipe by Lab-A-Porter

Challenges in research on human stomach and gastric cancer

  • The large discrepancies in physiology between animal and human stomachs have exerted challenges in the translation of physiological discoveries and drug screening.
  • Historically, gastric epithelial tissue is difficult to culture. [1]
  • The lack of accurate experimental platforms is one of the major difficulties in advancing more effective treatments for human cancers. [1]
  • There are limitations in using standard 2-dimensional cultured human cell lines in investigating drug responsiveness
      • These tools are prone to genotypic drift and cross-contamination [1]
      • It may result in failing to create permanent cell lines after long-term culture [1]
      • It can cause loss of tumour heterogeneity [1]

Opportunities on organoid technology in scientific research

In the last 10 years, researchers have employed gastric organoids in wide ranges of research areas, such as basic stomach biology research, the study of pathogens like Helobater pylori and gastric cancer research

Particularly, patient-derived organoids biobanks of gastric cancer act as a useful tool in studying gastric cancer biology

  • Gastric cancer ranking as the fifth most common malignancy, resulting in about 770,000 global deaths in 2020 alone [1,2]
  • Gastric cancer is a heterogenous disease displaying many different histological and molecular subtypes [1,3]
  • ‘One size fits all’ standard treatments are poorly suited due to the heterogeneous nature of gastric cancer [1,3]
  • Patient-derived organoids biobanks grant individualized in vitro therapy and resistance testing [2]
  • In a journal article published in 2018 by Cell Stem Cell, it is reported that scientists can successfully establish a biobank of patient-derived gastric cancer organoids. They included diverse subtypes which can be kept on long-term similarity to the organoid tumours. The establishment of a biobank can provide opportunities for:
      • Organoids as models to investigate tumour evolution and heterogeneity [3]
      • Organoid culture to predict drug sensitivity and as a tool for predictive testing to guide treatment, with the turnaround time for each organoid screen using 37 anti-cancer drugs took less than 2 weeks [3]

    Application of gastric organoids in research

    1. Use organoids as a preclinical model

    It can be built from human and animal cells and tissues, recapitulating more of the cellular complexity of actual tissues [1]

    2. Use human and mouse organoids for disease modelling

    For example, the use of gastric organoids has facilitated many important discoveries regarding H. pylori pathogenesis [1], pediatric gastric homeostasis and pediatric mucosal diseases [7]

    3. Use patient-derived organoids to personalize medicine for gastric cancer patients

    Patient-derived organoids retain the heterogeneity and histological characteristics of the primary tumour, representing an ideal model for drug screening [1]

    Establishing large patient-derived organoid libraries function as living banks and combining them with drug screening might be a powerful tool to delineate novel therapeutic strategies in gastric cancer [1]

    4. Use gastric organoids from endoscopic biopsies for drug testing and for therapy prediction and guidance [1]

    A novel technique published by scientists in establishing gastric organoids from endoscopic biopsies. [1]

    Scientists make gastric organoids with smooth muscle contraction

    In recent news articles of BioWorld and Cincinnati Children’s Research Horizons reported that scientists have successfully used human induced pluripotent stem cells (iPSCs) to create gastric organoids with three-layered structure and gastric function such as smooth muscle contraction and glandular secretion, of which these scientific findings have been recently published in Cell Stem Cell. [8,9]

      • The lab-grown tissue mirrored naturally grown human tissue at similar stages of development [8,9]
      • Scientists found out components needed to build stomach tissue with the suitable complexity and functions [8,9]

    Using gastric epithelium organoids with the CRISPR technology

    In a journal article published by PNAS, scientists use mouse gastric epithelial organoids with the CRISPR technology to identify modulators of Wnt-driven stem cell-dependent epithelial renewal in gastric mucosa

      • It provides insights into gastric epithelial differentiation [5]

    Example on limitation of current gastric organoid technology

    One challenge in using organoids is the difficulty in accessing the apical, or luminal, the surface of the epithelium, which are confined within the organoid interior

      • An article published by Nature Protocols in November 2021 detailly described how to control the polarity of human gastrointestinal organoids in suspension culture to investigate epithelial biology and infectious diseases [6]

    Some future trends on gastric organoid technology

    Techniques for how to best recapitulate the stomach’s physiology are rapidly evolving [1]

    • Soon, additional bioengineering approaches such as live imaging, genome editing, and single-cell genomics may also be incorporated into current organoid systems to better study human organogenesis, disease, and personalized medicine. [1]
    • Further incorporation and integration of microenvironment components, such as immune components, will allow gastric organoids and tumoroids to better represent in vivo physiology. [1]

    Selected compositions for gastric organoid culture recipe by Lab-A-Porter

    EGF

    EGF is a potent growth factor that stimulates the proliferation of various epidermal and epithelial cells. It has been shown to inhibit gastric secretion and be involved in wound healing.

    FGF-10

    FGF-10 is a heparin-binding growth factor that belongs to the FGF family. Proteins of this family play a central role during prenatal development, postnatal growth and regeneration of a variety of tissues.

    Noggin

    Noggin belongs to a group of diffusible proteins that bind to ligands of the TGF-β family and regulate their activity by inhibiting their access to signalling receptors.       

    R-Spondin-1

    R-Spondin-1 is expressed in certain areas of the developing central nervous system, as well as in the adrenal glands, ovary, testis, thyroid, and trachea.  

    Wnt-3a

    Wnt-3a signalling is essential for various morphogenetic events, including embryonic patterning, cell determination, cell proliferation, CNS development, and cytoskeletal formation.

    Gastrin

    Gastrin is a peptide hormone that is a major physiological regulator of the gastric acid section and a promoter of gastric mucosal growth. 

    Y 27632

    Y-27632 is a selective inhibitor of Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) family of protein kinases that selectively competes with ATP for binding to the catalytic site. 

    A 83-01

    A 83-01 is a potent activating receptor-like kinase inhibitor (ALK4 IC50 45nM, ALK5 IC50 12nM, ALK7 IC50 7.5nM). It is a more potent inhibitor of ALK5 than SB 431542 and is reported to inhibit Smad signalling and epithelial-to-mesenchymal transition by transforming growth factor-beta. 

    Nicotinamide

    Nicotinamide is an amide of nicotinic acid, a vitamin of the B complex. In cells, it is incorporated into NADP+ and NAD+, coenzymes for a wide variety of enzymatic oxidation-reduction reactions.

    SB 202190

    SB 202190 is a selective and potent p38 MAP kinases inhibitor, binding to its ATP pocket. It has negligible inhibiting properties on other MAP kinases such as ERKs and JNKs. 

    Xeno-free (animal origin-free) hydrogel system for organoid culture

    Ready-to-use, xeno-free (animal origin-free) hydrogel system for organoid culture

    Biogems, theWell Bioscience and Peprotech products are for research use only (RUO) and are NOT FOR THERAPEUTIC OR DIAGNOSTIC USE. 

    References:

    1. Pang, Min-Jiao et al. “Gastric Organoids: Progress and Remaining Challenges.” Cellular and molecular gastroenterology and hepatologyvol. 13,1 (2022): 19-33. doi:10.1016/j.jcmgh.2021.09.005
    2. Seidlitz, Therese et al. “Gastric organoids-an in vitro model system for the study of gastric development and road to personalized medicine.” Cell death and differentiationvol. 28,1 (2021): 68-83. doi:10.1038/s41418-020-00662-2
    3. Yan, Helen H N et al. “A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening.” Cell stem cellvol. 23,6 (2018): 882-897.e11. doi:10.1016/j.stem.2018.09.016
    4. Lo, Yuan-Hung et al. “A CRISPR/Cas9-Engineered ARID1A-Deficient Human Gastric Cancer Organoid Model Reveals Essential and Nonessential Modes of Oncogenic Transformation.” Cancer discoveryvol. 11,6 (2021): 1562-1581. doi:10.1158/2159-8290.CD-20-1109
    5. Murakami, Kazuhiro et al. “A genome-scale CRISPR screen reveals factors regulating Wnt-dependent renewal of mouse gastric epithelial cells.” Proceedings of the National Academy of Sciences of the United States of Americavol. 118,4 (2021): e2016806118. doi:10.1073/pnas.2016806118
    6. Co, Julia Y et al. “Controlling the polarity of human gastrointestinal organoids to investigate epithelial biology and infectious diseases.” Nature protocolsvol. 16,11 (2021): 5171-5192. doi:10.1038/s41596-021-00607-0
    7. Jones, Brendan C et al. “Paediatric gastric organoids as a tool for disease modelling and clinical translation.” Pediatric surgery internationalvol. 37,3 (2021): 317-324. doi:10.1007/s00383-020-04821-x
    8. Nag, Subhasree. Stomach organoid created from multiple stem cell types. ‘’ https://www.bioworld.com/articles/514157-stomach-organoid-created-from-multiple-stem-cell-types’’. BioWorld. December 2021.
    9. Eicher, Alexandra and Wells, James. New assembly approach generates most complex stomach organoids to date. ‘’ https://scienceblog.cincinnatichildrens.org/new-assembly-approach-generates-most-complex-stomach-organoids-to-date/’’. Cincinnati Children’s Research Horizons. December 2021.

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