Organoids are three-dimensional structures grown in the laboratory that mimic the organization and function of human organs. They are developed from stem cells and can replicate specific tissue characteristics, such as genetic mutations and cellular behaviors.
This makes them valuable tools for studying diseases and testing treatments in a controlled environment.
a) From human cancer tissue, tumor cells can be isolated and cultured to produce spheroids. b) Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are two common types of stem cells used as cell sources for organoid production. Both ESCs and iPSCs can form a variety of organoid models when given the right signaling cues and specific extracellular matrix (ECM). Image: Vanessa Velasco, S. Ali Shariati & Rahim Esfandyarpour
The first organoids were created in the early 2000s, with major breakthroughs in 2013 when Madeline A. Lancaster and her collaborators at the University of Cambridge developed brain organoids from pluripotent stem cells. Before that in 2009, pioneering research, such as that of scientist Hans Clevers, had already generated simpler models of organoids, such as intestinal ones, from stem cells.
Recently, organoid research has benefited from several technological innovations. One approach is the combination of epithelial organoids with other types of cells, such as immune cells, fibroblasts or neurons. This increases the complexity of the models, allowing a more faithful representation of human tissues and diseases.
First Brain Organoid. Source: M. Lancaster et al. Nature, volume 501, pages 373–379 (2013)
Another innovation is the use of CRISPR–Cas9 technology, which allows specific genes to be edited within organoids. For example, scientists genetically modified human liver organoids to study mutations associated with a rare and aggressive type of liver cancer, fibrolamellar carcinoma. They found that the combined loss of two genes, BAP1 and PRKAR2A, plays a crucial role in the development of this disease.
3D and 4D bioprinting are promising techniques. They allow the creation of larger and more complex organoid structures by arranging different cell types in specific patterns. This allows organoids to develop more dynamically, better mimicking the behavior of living tissues, such as stiffness and the presence of growth factors.
3D Bioprinting of Organoids
Artificial intelligence (AI) is also beginning to play a role in organoid research. AI models can analyze large amounts of data generated from organoid experiments, helping to identify patterns and predict responses to treatments.
On the other hand, organoids can provide more representative data to train AI models, improving their accuracy in biomedical applications.
One of the most promising applications of organoids is in personalized medicine. Because they can be grown from cells from a specific patient, organoids reflect the unique characteristics of that individual’s disease, increasing the chances of therapeutic success and reducing side effects.
Patient-derived organoids have been established for a variety of cancers, including colorectal, prostate, pancreatic, stomach, liver, biliary tract, breast, and neuroendocrine tumors.
Drug screening using these organoids is ongoing, making them powerful tools for discovering new treatments and personalizing cancer therapy.
Human liver organoid. Meritxell Huch. The Gurdon Institute
In October 2024, a search of the ClinicalTrials.gov database identified 36 ongoing clinical trials using organoids to develop personalized approaches to cancer treatment.
Some of these studies have already reached phase 3, the final stage before approval for clinical use. This means that, in the future, these models could be incorporated into medical practice, enabling more effective and individualized therapies for cancer patients.
One of the challenges in modeling cancer with organoids is the complexity of tumors, which are composed not only of cancer cells, but also of supporting cells, such as fibroblasts and immune cells.
Innovative treatments, such as immunotherapy, face difficulties in traditional organoids, as these models do not include the immune components and extracellular matrix present in real tumors, limiting the assessment of the efficacy of treatments.
To overcome this challenge, next-generation organoids are being developed that incorporate these components, allowing us to assess how immune cells, such as T cells, interact with tumor cells.
Prostate cancer organoids pave the way for precision oncology.
Over the past 15 years, organoid research has also led to significant advances in the study of reproductive health.
Scientists have been able to create organoids from different parts of the female reproductive system, including the ovaries, fallopian tubes, endometrium (the tissue lining the uterus), cervix and placenta.
These models have been used to study diseases such as cervical cancer, endometriosis, infertility and preeclampsia (a dangerous condition that can occur during pregnancy).
In addition to the female reproductive system, researchers have also developed testicular and prostate organoids to study male reproductive biology. These organoids have been used to form biobanks and to predict the effectiveness of treatments, helping to plan clinical trials.
Scientists are also exploring the use of organoids to study fetal development and possible congenital diseases. One promising discovery was the creation of organoids from amniotic fluid collected during pregnancy.
Fetal lung organoids generated from human amniotic fluid. Source: GIUSEPPE CALÀ, PAOLO DE COPPI, MATTIA GERLI
This means that in the future, doctors will be able to monitor the development of fetal organs and identify potential health problems in the baby early. Currently, prenatal diagnostic techniques include imaging, genetic testing and biochemical analysis, but none of these approaches can directly assess how the fetal organs are developing.
Organoids are also becoming an essential tool for understanding how environmental pollutants affect our health. Because epithelial tissues (those that line the body’s organs and surfaces) are the first to come into contact with harmful substances in the environment, epithelial organoids are being used to study the toxicity of pollutants and drugs.
Recent research has already shown that organoids can be used to assess the risks of substances such as microplastics and airborne particles, which can cause damage to the lungs and heart; chemicals such as bisphenol A and phthalates, which can affect the mammary glands and other organs; nanoparticles, which can be toxic to the kidneys and liver.
Over the past 100 years, pandemics caused by viruses have occurred frequently, causing millions of deaths. Many of these viruses come from animals and can reappear unexpectedly. To better understand how these infections occur and to seek treatments, scientists have used organoids.
These organoids were essential in studying the Zika virus, helping to confirm its link to microcephaly in babies. During the COVID-19 pandemic, they allowed us to analyze how the virus attacked different organs, such as the lungs, kidneys and liver. More recently, they were used to study the infection of the skin and kidneys by the mpox virus.
The rotavirus-infected gut organoid was stained with markers for rotavirus proteins (red), surface proteins (green), junctional proteins (magenta), and cell nuclei (blue). Images were acquired using confocal microscopy. Video courtesy of the J.T. Gebert/Hyser lab.
In addition to helping us understand how viruses act in the human body, organoids are also useful in the development of drugs and vaccines. They can be used to test antivirals and even to assess how the immune system responds to vaccines. Another important application is the search for new viruses that can jump from animals to humans, which could help prevent future pandemics.
Aging populations pose health challenges as the body loses its ability to regenerate itself. Organoids are used to study the accumulation of mutations over a lifetime and understand how this affects different organs. They also help identify potential treatments for age-related conditions such as pulmonary fibrosis and liver failure after transplants.
Intestinal Organoid. Kevin O’Rourke and Lukas Dow. Weill Cornell Medicine
In space research, organoids allow us to study the effects of microgravity and radiation on the human body. This is important both for the health of astronauts and for better understanding accelerated aging processes. Despite the technical challenges, such as maintaining these cultures in space, these studies could lead to advances in both space travel and treatments on Earth.
Regenerative medicine research is expanding rapidly, as it shows great potential for studying diseases and testing personalized treatments. Organoids derived from a patient’s own cells (called autologous cells) can be used for cell therapies, without the risk of rejection or adverse effects.
This opens up new possibilities for regenerative treatments, as they can be used in different types of diseases based on the patient’s genetic material.
To date, three important clinical trials have been conducted with organoids, focusing on treatments for diseases such as ulcerative colitis, diabetes, and xerostomia (dry mouth caused by radiation in cancer patients).
A successful example is the use of salivary gland organoids to treat dry mouth caused by radiation therapy in head and neck cancer patients. This treatment uses stem cells to regenerate salivary glands damaged by radiation, improving saliva production and improving patients’ quality of life.
In 2022, the first patient was treated with autologous cells derived from salivary gland organoids. This was the first phase 1-2 clinical trial using organoids in humans to prevent side effects of radiation, representing an important milestone in the use of organoids in regenerative medicine.
Organ transplants are essential for patients with end-stage organ failure, but there is a severe shortage of organs available for transplant. Organoids could help fill this gap by offering a way to repair damaged organs and even regenerate parts of organs such as livers.
These “epicardioids”—organoids made from pluripotent stem cells—are just 0.5 millimeters in size. Researchers can use them to mimic human heart development in the lab and study inherited heart diseases. Image: Alessandra Moretti
Studies are underway to explore the use of organoids in liver, kidney, heart, and lung transplants. While promising, these treatments are still in their early stages, and more research is needed to understand the full impact of these therapies.
Despite the promise, clinical use of organoids faces technical challenges. Starting organoid cultures from tissue biopsies or body fluids, such as bile or urine, is possible, but not always efficient.
Scaling up organoids on a large scale for clinical treatments is also a challenge, as it is an expensive and time-consuming process that requires large amounts of material and can raise environmental concerns.
Live brain organoid. Image: Universität Zürich
The use of organoids also raises important ethical issues, especially regarding the collection and use of patient cells. For example, it is necessary to decide how to ensure informed consent from cell donors and how to handle the genetic information of each patient.
Additionally, advances in organoids raise the question of replacing animal testing with more ethical and accurate methods, such as the use of organoids.
In a commercial context, the use of organoids can generate benefits, but it can also raise questions about the fair distribution of profits and benefits among researchers, patients and companies.
In short, organoids have brought about a revolution in stem cell biology and the study of diseases in a short period of time. The technology promises to expand its applications not only in regenerative treatments and organ transplants, but also in the study of infectious diseases and environmental effects on health.
While there are still challenges to be addressed, ongoing innovations suggest that organoids will be a crucial part of personalized and regenerative medicine in the future.
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Clinical applications of human organoids
Monique M. A. Verstegen , Rob P. Coppes , Anne Beghin, Paolo De Coppi , Mattia F. M. Gerli, Nienke de Graeff, Qiuwei Pan, Yoshimasa Saito, Shaojun Shi,
Amir A. Zadpoor & Luc J. W. van der Laan
Nature Medicine. 03 February 2025
Abstract:
Organoids are innovative three-dimensional and self-organizing cell cultures of various lineages that can be used to study diverse tissues and organs. Human organoids have dramatically increased our understanding of
developmental and disease biology. They provide a patient-specific model to study known diseases, with advantages over animal models, and can also provide insights into emerging and future health threats related to climate change, zoonotic infections, environmental pollutants or even microgravity during space exploration. Furthermore, organoids show potential for regenerative cell therapies and organ transplantation. Still, several challenges for broad clinical application remain, including inefficiencies in initiation and expansion, increasing model complexity and difficulties with upscaling clinical-grade cultures and developing more organ-specific human tissue microenvironments. To achieve the full potential of organoid
technology, interdisciplinary efforts are needed, integrating advances from biology, bioengineering, computational science, ethics and clinical research. In this Review, we showcase pivotal achievements in epithelial organoid research and technologies and provide an outlook for the future of organoids in advancing human health and medicine.
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