Enteroids are miniature, organ-like structures grown in a laboratory setting that closely resemble the human small intestine. These scientific models originate from intestinal stem cells, which possess the unique ability to self-organize and develop into complex tissues. Enteroids provide a controlled environment for researchers to study the human gut, offering insights into its normal function and various disease states. Their ability to mimic the intricate structure and cell diversity of the human intestine makes them invaluable tools in biological research.
What Enteroids Are and How They Are Grown
Enteroids are three-dimensional cellular structures that self-organize to form mini-intestines. They are primarily derived from Lgr5+ intestinal stem cells, which are found at the base of intestinal crypts in the small intestine or colon. These stem cells possess the capacity to self-renew and differentiate into all the specialized cell types found in the intestinal lining.
The process of growing enteroids involves isolating these intestinal stem cells, often from surgical specimens or biopsies, and embedding them in a specialized extracellular matrix, such as Matrigel. The cells are then submerged in a growth medium enriched with specific factors like Wnt3a, R-spondin, and Noggin, which mimic the natural signals that support stem cell division and differentiation in the body. These stem cells proliferate and spontaneously form polarized spheroid-like structures that develop crypt-like domains and villus-like protrusions, closely resembling the anatomy of the human gut. These structures contain various intestinal cell types, including absorptive enterocytes, mucus-producing goblet cells, hormone-secreting enteroendocrine cells, and antimicrobial peptide-producing Paneth cells, in proportions similar to those found in the actual intestine.
Why Enteroids Are a Breakthrough
Enteroids represent a significant advancement over traditional research models due to their ability to accurately replicate human intestinal physiology. Unlike two-dimensional cell cultures, which are often derived from cancer cells and lack the complex cellular diversity and three-dimensional architecture of the gut, enteroids maintain the in vivo characteristics of human intestinal epithelium, even after many passages. This means they contain all the major epithelial cell types found in the intestine, allowing for a more comprehensive understanding of cellular interactions and functions.
Animal models, while providing a systemic response, can be resource-intensive and often fail to accurately predict human drug responses due to inherent mechanistic differences between species. Approximately 90% of drugs tested in animal models fail in human clinical trials, highlighting the need for more human-relevant systems. Enteroids overcome these limitations by offering a human-derived, three-dimensional model that exhibits functions like nutrient and ion transport, barrier integrity, and mucus secretion, mirroring the actual human gut more closely. Their human relevance leads to more accurate and translatable research findings, accelerating drug development and reducing costs associated with failed clinical trials.
How Enteroids Are Being Used
Enteroids are extensively used to study various gut diseases, providing insights into their underlying mechanisms and potential treatments. For instance, they serve as models for inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis, enabling researchers to investigate how epithelial barrier dysfunction contributes to these conditions. Enteroids have also been instrumental in studying infections caused by enteric bacterial pathogens such as Shigella, Salmonella, and Vibrio cholerae, as well as viruses like rotavirus and norovirus. They allow for the examination of host-pathogen interactions, including how pathogens invade cells and the host’s inflammatory response.
Beyond disease modeling, enteroids are valuable for drug discovery and testing. They can be grown as polarized monolayers, providing direct access to the apical and basolateral surfaces, which is useful for studying drug absorption and toxicity. This enables high-throughput screening of potential drug candidates, leading to more efficient identification of effective therapies. For example, enteroids have been used to test compounds for necrotizing enterocolitis (NEC), a severe intestinal condition in premature infants, offering a promising preclinical model for treatment testing. The ability to derive enteroids from individual patients also supports personalized medicine approaches, allowing researchers to study patient-specific disease characteristics and predict individual responses to therapies. In regenerative medicine, enteroids hold promise for repairing damaged intestinal tissues, with preclinical studies demonstrating their potential for functional integration and epithelial restoration when transplanted into animal models.