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Light microscopy image of a culture of patient-derived colon normal organoids embedded in Matrigel. Scale bar: 500 mm.

What? Organoids are small, three-dimensional structures that are grown in a laboratory and are used to study the development and function of organs. They are typically generated by stem cells (adult tissue, embryonal, pluripotent induced, or cancer stem cells) cultured in a special medium and conditions that mimic their niche in vivo. To this, cells are incubated with a mix of growth factors, hormones, vitamins and other agents that are specific of the tissue of origin, and embedded in an extracellular matrix (usually Matrigel, of animal origin, or any of the synthetic ones under development). On the days following isolation, organoids contain a small proportion of stem cells together with their progeny of partial and terminally differentiated cell types that self-organize into a spherical structure that resembles the tissue of origin in terms of gene expression and intercellular communications.

Organoids are used in a variety of research and clinical settings, including cancer research, drug testing and development, and regenerative medicine. They can be used to model the development and function of normal organs, as well as to study the effects of diseases, toxins, or other environmental factors on tissue/organ physiology and pathology.

Organoids have several advantages over traditional cell cultures or animal models. They are genetically stable during prolonged periods of time and can be safely stored frozen to be thawed at desired, which allows longitudinal studies. Thus, organoids more accurately mimic the structure and function of an organ than classical cell lines, and can be used to study human-specific processes that may not be possible to study in other models. In addition, organoids can be generated from a variety of sources, including patient-derived tissues permitting the study of individual patient characteristics and the development of personalized therapies (Barbáchano et al., 2021; Zhao, 2022).

Overall, organoids are a powerful tool for understanding organ development and function, and they revolutionizing our understanding of human biology and the treatment of diseases as they allow to compare paired normal and diseased (inflamed, tumoral…) tissue of the same individual.

Who? Today, there are many researchers and clinicians working with organoids in a clinical setting in a large variety of fields, from cancer research to regenerative medicine. Here are a few examples of pioneer studies that have used organoids in a clinical setting:

• Cancer research: Organoids have been used to study the genetics and drug sensitivity of cancer cells and to test potential new treatments for cancer. For example, a study published in the journal Cell in 2015 used organoids to test the effectiveness of around 80 chemotherapy drugs on patient-derived colon cancer cells (van de Wetering et al., 2015). Recent review in the field by Munro et al., 2023.
  
•      Regenerative medicine: Organoids have been used to study the potential for regenerating damaged or diseased organs. For example, a study published in the journal Science in 2018 used organoids to investigate the potential for regenerating damaged pancreatic tissue in patients with diabetes (Prickett et al., 2018). Recent review in the field by Choi et al., 2023.

When? Organoids have been used in medical research for several decades, but their use in clinical settings is more recent. For instance, organoids were already used in 2009 in the study of the development and function of the human intestine (Sato et al., 2009), then in 2011, to study the development and function of the human liver (Huch et al., 2011) and later in 2013, to investigate the development and function of the human pancreas (van den Brink et al., 2013). These early studies laid the foundation for the use of organoids in medical research and helped to establish their potential as a tool for studying human development and disease. Since then, the use of organoids in medical research and clinical settings has continued to grow, and they are now being used in a variety of research and clinical settings, including cancer research, drug development, and regenerative medicine.

Where?  How? Organoids are today extensively used in many laboratories around of the world looking for new disease insights. Organoids are used in a variety of research studies, including academic and industry laboratories, as well as hospitals and clinical research centers. They constitute new, valuable tools to study a wide range of diseases and conditions, including cancer, cardiovascular disease, and neurological and gastrointestinal disorders.

In the field of cancer research, organoids are used to study the development and progression of various types of cancer, to test the effectiveness of chemotherapy drugs and to understand the mechanisms of resistance to chemotherapy. In the field of cardiovascular research, organoids have been used to study the development and function of the heart, as well as to understand the mechanisms of and potential therapies for heart diseases. In the field of neurological research, organoids are used to study the development and function of the brain, as well as to understand the mechanisms of neurological disorders such as Alzheimer's disease and Parkinson's disease.

The use of organoids in the field of gastroenterology is a rapidly growing area of research, and there is great potential for organoids to revolutionize the way that we understand and treat digestive disorders and analyze the biology of normal and cancer stem cells (Fernández-Barral et al., 2020). Here are a few examples of current and future directions for the use of organoids in gastroenterology:

• Personalized medicine: Organoids can be generated from colorectal patient-derived normal and tumor tissue, which allows for the study of individual patient characteristics and the development of personalized therapies (Barbáchano et al., 2021; Wensink et al., 2021).
• Drug development and resistance: Organoids can be used to test the safety and efficacy of new drugs in a more accurate and human-specific way than traditional animal models. Thus, a study published in the Journal of Gastroenterology used organoids to test the effectiveness of new drugs for the treatment of ulcerative colitis (Nishimura et al., 2019), and the applications to investigate chemotherapy resistance are collected in a recent review (Harada and Sakamoto, 2022).
• Regenerative medicine: In a pioneering study published in the journal Nature Medicine, the transplant capacity of these organoids was tested in mice. Colon organoids were reintroduced into damaged mouse intestine. The transplanted organoids successfully integrated into the mouse colon, covering the area of damaged epithelium (Yui et al., 2012). Recent reviews in the field by: Nakamura, 2019; Oda et al., 2022; Okamoto et al., 2023.
  
  
  

Did you know that… although organoids are thought to recapitulate the development of organs in vitro, technical limitations still exist to ensure reproducibility and accurate replication of the complexity of human organs at scale.


A look to the future: The Potential of Organoids in Gastroenterology and Surgery
Organoids have the potential to transform the way that we understand and treat digestive disorders, and their use in the field of gastroenterology is an exciting area of research with many potential applications. They can be used to study the development and function of the gastrointestinal tract, as well as to understand the mechanisms of gastrointestinal diseases.

One promising application of organoids in gastroenterology is in the study of inflammatory bowel disease (IBD). IBD is a chronic condition that affects the digestive system and can cause symptoms such as abdominal pain, diarrhea, and weight loss. Organoids can be used to study the development of IBD and to identify potential therapeutic targets for the treatment of this condition. For example, a study published in the journal Inflammatory Bowel Diseases used organoids for modeling epithelial barrier and to study development of epithelial-targeted therapies (Jelinsky et al., 2023).

In the field of surgery, organoids have the potential to be used in a variety of applications, including tissue engineering and personalized medicine. For example, organoids could be used to create functional tissues for use in transplantation or tissue repair, once the use of animal extracellular matrix can be safely replaced by compatible matrix, or to create personalized treatment plans based on an individual's specific genetic makeup.

Overall, the use of organoids in the fields of gastroenterology and surgery has the potential to significantly advance our understanding of these fields and to improve patient care. However, there are also limitations to the use of organoids, including the fact that presently organoids basically contain epithelial cells and thus, they do not fully replicate the complexity of human organs and may not accurately reflect the response of human tissues to certain stimuli. However, an intense ongoing effort of many laboratories is nowadays focused on the generation more complex, heterotypic organoids containing also mesenchymal (e.g., fibroblasts…), endothelial, immune and nerve cells aiming to get closer to the in vivo condition (Zhao, et al., 2022).

Supplementary Figure:

References

Barbachano A, Fernandez-Barral A, Bustamante-Madrid P, Prieto I, Rodriguez-Salas N, Larriba MJ et al. Organoids and Colorectal Cancer. Cancers (Basel) 2021; 13.

Zhao ZC, X.;  Dowbaj, AM.; Sljukic, A.; Bratlie, K.;, Lin, L.; Fong,  ELS.; Balachander, GM.;  Chen, Z.;  Soragni, A.; Huch, M.;  Zeng, Y.A.;  Wang, Q.; & Yu, H. Organoids. Nature Reviews Methods Primers 2022; 2.

van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015; 161: 933-945.

Munro MT, Tan ST; Gray, C. Applications for Colon Organoid Models in Cancer Research. Organoids 2023; 2(1): 34-37.

Choi WH, Bae DH, Yoo J. Current status and prospects of organoid-based regenerative medicine. BMB Rep 2023; 56: 10-14.

Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology 2011; 141: 1762-1772.

Jung P, Sato T, Merlos-Suarez A, Barriga FM, Iglesias M, Rossell D et al. Isolation and in vitro expansion of human colonic stem cells. Nat Med 2011; 17: 1225-1227.

Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 2013; 494: 247-250.

Boj SF, Hwang CI, Baker LA, Chio, II, Engle DD, Corbo V et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 2015; 160: 324-338.

Fernández-Barral A, Costales-Carrera A, Buira SP, Jung P, Ferrer-Mayorga G, Larriba MJ et al. Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids. FEBS J 2020; 287: 53-72.
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