Assembloids are advanced three-dimensional biological models that combine multiple types of organoids or cell populations to replicate complex tissue interactions in a laboratory setting. They offer a new way to study how different parts of an organ or various cell types communicate and interact, which is difficult to observe with simpler models. Assembloids provide more accurate representations of human biology outside the body, allowing scientists to gain deeper insights into how tissues form and function, and how diseases develop.
Building Blocks of Assembloids
Organoids are miniature, self-organizing three-dimensional tissues grown from stem cells. These structures, typically ranging from hundreds of micrometers to a few millimeters, mimic specific organs or parts of organs, such as the brain, gut, or kidney. They develop from pluripotent stem cells, which have the ability to differentiate into various cell types, and self-assemble into complex structures that retain cellular diversity and architectural features of the original tissue. While organoids significantly advance the study of individual organ systems, they often do not capture intricate interactions between different tissues or cell lineages within a living organism.
Assembloids represent a progression beyond single organoids, formed by combining two or more distinct organoids or tissue types. This combination allows for the study of interactions between different cell populations or brain regions that communicate in the body. For instance, a brain assembloid might fuse a cortical organoid with a thalamic organoid to observe how these distinct brain regions connect and communicate. This approach enables researchers to investigate complex biological processes like cell migration and neural circuit formation, providing a more comprehensive model than individual organoids alone.
Crafting Assembloids
Assembloids begin with pluripotent stem cells, such as human induced pluripotent stem cells (hiPSCs) or human embryonic stem cells (hESCs). These stem cells are guided through differentiation protocols to become specialized cell types, which then self-assemble into individual organoids. For example, in the creation of a brain assembloid, stem cells might be directed to form a cortical organoid and a subpallial organoid, representing different regions of the developing brain.
Once individual organoids are formed, they are brought together in co-culture conditions. The organoids then spontaneously fuse, allowing cells from one to migrate into and interact with cells from another. This process is influenced by growth factors and culture medium formulations, controlled to encourage inter-organoid connections and functional neural circuits or other tissue interactions. For instance, in a forebrain assembloid, interneurons from the ventral forebrain organoid can migrate and integrate into the dorsal cortical organoid, forming synaptic connections.
Unlocking Biological Insights
Assembloids advance scientific discovery by enabling the modeling of complex biological processes and diseases that single organoids cannot fully capture. They offer a platform to study how different brain regions connect and communicate, providing insights into brain development and connectivity. For example, assembloids have been used to observe interneuron migration from the subpallium into the cortex, a crucial step in human brain development.
These multi-organoid systems are valuable for investigating neurodevelopmental disorders like autism and schizophrenia, where disruptions in inter-regional communication are suspected. For instance, assembloids derived from patients with Timothy syndrome, a genetic disorder, have shown impaired interneuron migration, revealing how this defect impacts neural circuit formation. Assembloids also serve as models for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, allowing scientists to study how interactions between different brain regions contribute to disease progression. Beyond neurological applications, assembloids model interactions in other tissues, such as the enteric nervous system or tumor microenvironments, facilitating drug screening and personalized medicine approaches by offering more accurate disease representations.
Navigating the Path Forward
Despite their promise, assembloid technology faces several limitations. Achieving full vascularization remains a challenge, limiting nutrient and oxygen delivery to the core of larger assembloids and potentially leading to cell death. Replicating the full complexity of an entire organ, with all its diverse cell types and intricate architecture, is also a hurdle. Furthermore, maintaining long-term stability and achieving standardization across different batches of assembloids are ongoing areas of research, as variability can affect experimental reproducibility.
Ethical considerations also arise with the creation of more complex, integrated biological models, particularly for brain assembloids. As these models become more sophisticated, questions about sentience or consciousness may emerge, necessitating ethical guidelines and public discourse. Despite these challenges, the future of assembloid research is promising, with ongoing efforts to improve their complexity and integrate them with bioengineering techniques. These advancements are expected to further refine assembloids as tools for understanding human biology and disease, potentially leading to new therapeutic discoveries and personalized treatment strategies.