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Organoid technology refers to using stem cells to induce three-dimensional tissue models directly and provides powerful method support for human biological research. Currently, the research on this tool is constantly developing and progressing. Especially in recent years, with the popularity of gene and cell therapy, organoid research is also in full swing.
Medicilon has established a complete pharmacology research platform based on animal disease models (including PDX models, xenograft tumor models, humanized tumor models, etc.) and, at the same time, continued to empower innovative therapies and deploy tumor immunotherapy. Medicilon has built a one-stop research platform for the preclinical R&D of cellular immunotherapies, covering a variety of immunotherapy methods, including CAR-T, TCR-T, and CAR-NK. Medicilon will also lay out a pharmacology research platform for organoids!
What is Organoid Technology?
Organoids are 3D cell cultures with highly similar histological features to human organs and can reproduce their physiological functions in-vitro; they are capable of cell proliferation and differentiation, self-renewal, self-assembly, long-term culture, and characteristics of genetic stability.
Compared with traditional 2D culture models, organoids represent an innovative technology capable of recapitulating the physiological process of the entire organism, with closer physiological cell composition and behavior, a more stable genome, more suitable for biological transfection, high-throughput screening, and other advantages. Compared with animal models, organoid models are easier to operate and can also be used to study the mechanisms of disease occurrence and development.
Organoid Technology Development
In 2009, a landmark study by Toshiro Sato et al. showed that adult intestinal stem cells could proliferate and spontaneously organize in-vitro. It is characterized by the ability to express LGR5, a gene encoding the Wnt agonist R-spondin receptor while requiring specific molecules to surround it, such as Wnt, epidermal growth factor, and noggin.
Based on this theory, the researchers developed a three-dimensional culture system that can reconstitute a suitable environment for intestinal stem cells in-vitro and differentiate from intestinal epithelial cells or single Lgr5+ stem cells with self-renewal ability, maintaining intestinal crypt-villus-shaped organoids. The model can be continuously expanded for up to three months, and the stable genome ensures the advantages of purification and production scale-up. Since then, this method has been used to prepare various organoids from epithelial tissues of other significant organs.
In 2013, researchers from Japan, Germany, and the United States constructed liver buds, mini-kidneys, and mini-brains, respectively, making this field gain international attention and being selected by Science as one of the top ten breakthroughs in 2013.
In 2017, organoid technology was named Technology of the Year in Life Sciences by Nature Method. Scientists have used stem cells to successively cultivate gastric fundus organoids, functional intestinal organoids, corneal organoids, organoids that simulate the structure and function of lungs, and colon organoids. Compared with traditional 2D/3D cell lines and animal models, organoids are extremely competitive in system construction, cycle time, cost, clinical consistency, and subsequent analysis.
Organoids Compared to Other Models
Although organoids have many advantages compared with traditional in-vitro/in-vivo models, there are still some technical difficulties to be solved in conventional organoid culture platforms, such as the inability to construct immune microenvironment models, the failure to reproduce the vascularization process, and the difficulty in realizing multi-organ interaction. Second, it isn’t easy to standardize the organoid culture system on traditional platforms. Hence, the reproducibility and stability of the model are low, and large-scale and automated applications are currently difficult to achieve.
Applications of Organoid Technology
So far, organoid technology has been widely used in several fields, including disease modeling, drug development, drug screening, etc. Under 3D culture conditions, various organoids, such as the lung, stomach, intestine, liver, kidney, etc., have been successfully cultured.
The enormous potential of organoid technology is also increasingly being exploited. Not only can it be used for drug toxicity testing, drug efficacy evaluation, and new drug screening, but also it can be used to establish disease models to study genetic diseases, infectious diseases, and tumors. It can also be used for precision medicine, tissue and organ development research, and tissue and organ transplantation and repair.
Model Building
Compared with two-dimensional culture systems, organoids help elucidate disease development, homeostasis, and pathogenesis and provide possible new methods for diagnosing and treating conditions. Taking brain organoids as an example, they include human-specific neurogenesis processes and provide valuable opportunities to study human brain development. This organoid model, grown in a microfabricated chamber for long-term in situ imaging, has been used to model cortical folding and explore the pathogenesis of flat brain disease.
Drug Screening
Corresponding organoids have been cultured from various primary tumor cells, and these tumor organoids have become important preclinical screening models that can predict an individual patient’s response to therapy. Tumor organoids link tumor-associated genomic data with tumor biology, providing a research basis for drug screening and personalized treatment.
Due to their high similarity to physiological tissues, organoids can simulate experimental drug responses to optimize treatment options, individualize treatment for patients, and evaluate drug toxicity, such as toxic effects on the heart, liver, and kidneys. Kidney and liver toxicity are the most frequently occurring organ toxicity, and artificially prepared kidney and liver organoids can provide a more accurate means for toxicity prediction.
Pharmacology
Organoid technology has great potential in pharmacology. Organoid technology can provide a reference for later clinical drug use. For example, if organoid drug sensitivity screening technology can be further developed, the effectiveness of tumor drug use will be significantly improved. Medicilon has established a complete pharmacology research platform based on animal disease models, and Medicilon will also deploy a pharmacology research platform for organoids!
For disease research
Organoid technology can currently be used in the research of genetic diseases, the study of infectious diseases, the research of neuropsychiatric disorders, and the precision medicine of tumors. Organoids are in-vitro 3D culture platforms constructed by self-assembling stem cells, which can almost precisely reproduce tumor heterogeneity and microenvironment. The organoid tumor model retains the molecular and cellular composition of the original tumor, which can more accurately predict the patient’s treatment response, enable preclinical drug screening, and develop a personalized treatment plan for the patient.
Boost gene/cell therapy
Functional organoid transplants have emerged in experiments with liver, pancreas, retina, and thyroid tissues. Genome editing has also been used to correct mutations in CFTR and restore CFTR protein function in colon organoids from cystic fibrosis patients. In the future of cell therapy, organoid technology will be one of the sources of tissue cells. However, more studies are needed to evaluate the effectiveness and safety of these methods, and bringing induced pluripotent stem cells to the clinic will be an essential direction of efforts.
What are the Prospects and Challenges of Organoid Technology
The long experimental cycle and high cost of drug screening and subsequent in-vivo drug evaluation are not conducive to the rapid advancement of drug development. Therefore, organoids, as an in-vitro cell model that can effectively evaluate drug pharmacological and toxicological effects, have received extensive attention from researchers.
The currently cultured organoids have begun to take shape, and because of their bright market application prospects, their development momentum is bound to be rapid. Organoids provide new platforms and tools for drug and disease research, can predict the therapeutic response and effect of drugs, and provide a basis for personalized treatment of patients.
Although remarkable progress has been made in organoid research, many challenges remain, including the complexity and variability of preparation methods and the lack of standardization. Fortunately, biotechnology is also developing rapidly, providing more means to solve these problems. Organoid technology has been effectively combined with other cutting-edge technologies, so it is of practical significance to use organoids to establish disease models and study tissue and organ development!
Reference:
[1]Toshiro Sato, et al. Single Lgr5 stemcells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009 May 14;459(7244):262-5.
[2] Jihoon Kim, et al. Human organoids: model systems for human biology and medicine. Nat Rev Mol Cell Biol. 2020 Oct;21(10):571-584.
[3] Nick Barker, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007 Oct 25;449(7165):1003-7.
[4] Hans Clevers. Modeling Development and Disease with Organoids. Cell. 2016 Jun 16;165(7):1586-1597.
[5] Claudia Corrò, et al. A brief history of organoids. Am J Physiol Cell Physiol. 2020 Jul 1;319(1):C151-C165.
