Organoids are miniature, self-organizing 3D tissue cultures grown in a laboratory. Derived from stem cells, they mimic the cellular composition and some functions of actual organs. While traditional organoids model a single organ or tissue type, “hub organoids” integrate multiple tissue types or model complex biological interactions, extending beyond a single organ’s scope.
Hub organoids replicate intricate physiological “hubs” found within the human body by connecting different cellular components. This allows for a comprehensive understanding of how various tissues communicate and interact. These integrated systems open new avenues for studying complex biological processes and diseases.
Understanding Hub Organoids
Hub organoids integrate diverse cell types and tissues into a unified, functional unit, unlike conventional single-organ organoids. Traditional organoids often replicate only the epithelial layer of a single organ, lacking surrounding stromal, immune, or vascular endothelial cells found in a complete organ.
The “hub” concept refers to their ability to model complex physiological interactions involving multiple tissue types. For example, a hub organoid might recreate aspects of the gut-brain axis or model multi-organ drug metabolism. This multi-cellular diversity and integrated 3D architecture allow for a more accurate representation of how different parts of the body communicate.
To achieve this complexity, hub organoids incorporate primary organ-specific cells alongside supporting cells like fibroblasts, immune cells, or endothelial cells. These additional cell types create a more complete microenvironment, enabling realistic cell-to-cell communication and tissue organization. The aim is to build a system reflecting the intricate network of interactions seen in living organisms.
Hub organoids derived from adult stem cells can be established without feeder cells, allowing for long-term cultures that preserve genomic and phenotypic identity. They can also be established more quickly than those from pluripotent or induced pluripotent stem cells, as they do not require additional reprogramming and differentiation steps.
Building Complex Systems
Creating hub organoids involves sophisticated techniques to guide the self-organization of different cell types into integrated structures. A challenge lies in co-culturing various cell populations while ensuring they maintain their identities and interact appropriately. Researchers must provide the right biochemical cues and physical environments for these diverse cells to assemble into a cohesive, multi-tissue unit.
Microfluidics plays a role by controlling fluids at a microscopic level, enabling precise manipulation of cells and biomaterials. Microfluidic devices, often miniaturized labs on a chip, mimic human tissue environments. This allows for controlled nutrient and waste exchange, and the creation of chemical gradients that guide cell differentiation and organization.
Bio-printing is another technique used to build hub organoids, enabling the precise placement of cells and biomaterials layer by layer. This method creates intricate 3D architectures difficult to achieve through self-assembly. Using bio-inks with living cells, extracellular matrices, and hydrogels, researchers can print scaffolds that guide multi-tissue constructs, ensuring correct spatial arrangement.
Specialized scaffolds, often hydrogels or other biocompatible materials, provide structural support and the necessary microenvironment for multi-tissue interaction and vascularization. These scaffolds can be engineered with specific stiffness, porosity, and biochemical properties that influence cell behavior. Forming these complex “hub” structures requires understanding developmental biology and tissue mechanics.
Transformative Applications
Hub organoids offer advancements in disease modeling, providing more accurate representations of complex conditions involving multiple organs or systems. They allow researchers to study neurological disorders like Alzheimer’s or Parkinson’s by recreating interactions between neuronal and supporting brain tissues. These models can also simulate cancers with distant metastases or metabolic syndromes like type 2 diabetes by integrating liver and pancreatic components.
In drug discovery and development, hub organoids serve as platforms for screening new therapeutic compounds. These integrated models predict drug efficacy and toxicity across multiple tissues, offering a more holistic view than traditional single-cell or single-organ models. This helps reduce reliance on animal testing, providing a more relevant preclinical assessment. For example, hub tumor organoids mirror original tumor properties, making them valuable for drug screens and predicting patient response.
Hub organoids are also transforming personalized medicine by enabling patient-specific models. By deriving organoids from a patient’s own tissues, researchers can create “mini-organs in a dish” that preserve unique genetic and phenotypic characteristics. This allows for testing various treatments on a patient’s own cells, predicting individual responses and tailoring treatment plans. This individualized approach helps determine which patients will respond to specific treatments, particularly in oncology.
Hub organoids provide insights into human development, especially for complex developmental processes and congenital conditions involving multi-organ interactions. They allow scientists to observe how different tissues develop, identifying mechanisms that govern organ formation and inter-organ communication. This understanding can lead to new strategies for addressing developmental disorders and regenerative medicine.
Advancing Organoid Technology
Ongoing research aims to improve the long-term viability of hub organoids, which is important for studying chronic diseases and developmental processes. Ensuring a stable microenvironment and sustained nutrient supply are focus areas. Researchers also work to enhance the functional maturation of these models, allowing them to more closely mimic adult organ functions.
Introducing vascularization is an objective to improve nutrient and waste exchange within larger hub organoids. Without a functional blood vessel network, organoids larger than 200-400 micrometers can suffer from limited oxygen and nutrient diffusion, leading to cell death. Strategies include co-culturing organoids with endothelial cells, directing stem cells to form vascularized organoids, or fusing pre-formed vascular spheroids with organoid components.
Integrating immune cells into hub organoids is another area of advancement, as immune responses play a substantial role in many diseases, including cancer and infectious conditions. Co-culturing tumor organoids with immune cells (e.g., T cells, macrophages, NK cells, B cells) allows for the study of immuno-oncology drug development and checkpoint inhibitors. This helps understand how the immune system interacts with diseased tissues and how immunotherapies might work.
The push towards creating more complex “organ-on-a-chip” or “human-on-a-chip” systems involves connecting multiple interacting hub organoids within a microfluidic platform. These systems can simulate systemic interactions between different organs, such as the liver-pancreas axis for metabolic studies, or the gut-brain axis. Standardized protocols for reproducibility are also being developed to ensure consistent and reliable research findings.