New Uses for Organoids
Why Organoids?
What are Organoids?
Organoids are self-assembled 3D structures derived from stem cells that can replicate certain features of organs. Organoids are produced by adult stem cells or induced pluripotent stem cells (iPSCs), and induced differentiation depends on the different expression profiles of cell adhesion molecules and the pedigree commitment of spatial limitations. Restricting cell space in tissues or using biological scaffolds to promote further differentiation of stem cells is critical in organoid generation. Biological scaffolds, such as basement membrane extracts, from Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells are most commonly used in the laboratory and provide environmental cues, including growth factors, that encourage cells to attach and form organoids. Small molecules are also widely used in culture medium to guide organoid growth and differentiation.
Organoids could be a particularly useful area for drug discovery. Organoids generated from patient-derived iPSCs have been found to reproduce disease features and are useful in preclinical screening of new therapies to establish efficacy at the cellular level. However, a recent paper by Pellegrini et al. offers a different perspective on how organoids can be used for drug screening.
Pellegrini and his team established ChP organoids by adapting the protocol for generating brain organoids from human iPSCs by adding BMP-4 and CHIR 99021 to mature media. The resulting organoids are enriched in the cubic epithelium and form fluid-filled chambers containing colorless liquids, similar in structure and function to the choroid plexus. Analysis of the colorless fluid revealed that it was very similar to cerebrospinal fluid. Structurally, ChP organoids have tight junctions, primary cilia, extensive microvilli, polyvesicles, and extracellular vesicles that are characteristic of CHPS.
These organoids have the potential to predict the central nervous system permeability of new therapies being developed to determine a compound's potential to treat neurological diseases or its possible toxicity. In vivo, the choroid plexus has different permeability to levodopa and dopamine. ChP organoids also showed different permeability to these compounds, with the former being transported into the organoids and the latter not, proving that this 3D system can be used to simulate CNS permeability of drugs as a proof-of-principle.
In 2016, clinical trials are underway in France for BIA 10-2474, a fatty acid amide hydrolase inhibitor that can be used in the treatment of various neurological disorders. Five participants in the trial developed severe acute neuropoisoning, and one died. The compound has not yet shown neurotoxic effects in animals, but ChP organoids from human iPSCs show a toxic accumulation of BIA 10-2474, revealing the potential use of the system in toxicity testing for novel therapies.
Organoids and Cancer Therapy
Tumor organoids of many different cancer types, such as breast, prostate, colon and endometrial cancers, have been generated from cancer biopsies of patients. Recently, Maenhoudt et al reported on the generation of ovarian cancer (OC) organoids from patients with high-grade severe ovarian cancer (HGSOC), using the approach of Boretto et al. (2019) to improve organoid establishment and growth.
These biopsie-derived tumor organoids exhibit the same phenotype as the primary tumor and recurrent disease. They provide a useful model for developing research into OC and can also be used to screen new treatments to determine their effectiveness against this type of cancer. However, there is another potential use for them, and that is personalised medicine. OC organoids from different patients showed different sensitivity to conventional chemotherapy agents such as paclitaxel, carboplatin, gemcitabine, and adriamycin. As such, they can be useful in clinical practice, enabling clinicians to choose the most effective treatment for individual patients.
Update: Organoids and COVID-19 Research
Since publishing the original paper, Pellegrini and his team have used CHP-like organs to learn more about COVID-19. The viral infection is characterized by severe respiratory symptoms, but some patients also experience neurological symptoms such as headaches, confusion and seizures. Pellegrini's team therefore examined the effects of SARS-CoV-2, or pseudovirions carrying SARS-CoV-2 spike proteins, on CHP-like organs and found that the virus mainly infected epithelial barrier cells of the choroid plexus, rather than neurons or glial cells. This results in epithelial cell damage and leakage of the blood-CSF barrier.
Reference
1.Boretto et al. (2019) Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol 21, 1041. PMID: 31371824
2.Maenhoudt et al. (2020) Developing organoids from ovarian cancer as experimental and preclinical models. Stem Cell Rep 14, 717. PMID: 32243841
3.Pellegrini et al. (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 369, eaaz5626. PMID: 32527923
4.Pellegrini et al. (2020) SARS-CoV-2 infects the brain choroid plexus and disrupts the blood-CSF barrier in human brain organoids. Cell Stem Cell 27 951. PMID: 33113348