Ex vivo organoid culture could revolutionize biology, but variability must be understood.
Imagine if biologists did not depend upon two-dimensional (2D) culture of transformed cell lines on glass or plastic and could instead study cellular processes in a more realistic ex vivo context. The day when this is widely a reality may not be too far off, given the explosive interest in the culture of organoids.
The term 'organoid' is used nowadays to describe ex vivo multicellular fragments that contain the major cell types of a particular organ and approximate its in vivo organization. They are typically generated by culturing multipotent or pluripotent stem cells in a three-dimensional (3D) matrix (most often Matrigel) under conditions that permit or promote self-organization of the cells. These conditions are determined experimentally but are often informed by prior knowledge of the signals that drive development or regeneration.
Organoids have been reported for a range of tissues—retina, kidney, intestine, stomach, lung, brain, and liver, to name just a few. As interest in the technology grows, research efforts are geared toward improved maturation, even to the point of attempting to integrate immune cells and blood vessels into the structures. Increasingly, researchers are also growing organoids from primary tumors, either as models for tumor biology or as a more realistic system for in vitro drug screens.
These developments are important. But the technology will stand or fall with the ability to understand variability in the outcomes, correct for it, and ideally control it. We already know from work with differentiating pluripotent stem cells in 2D that factors inherent to a cell line can contribute to variability. This is likely to only be compounded when growing more complex 3D self-organizing structures, for which even quantitative measures of correct structure and function are still being defined. Work geared toward improved control of the process, such as with defined matrices, will be important, as are attempts to understand organoid formation using the arsenal of research techniques—gene editing, imaging—now available to biologists.
The very origins of cell culture lie in 'tissue culture', in attempts to grow out cells from tissue explants. With a return to methods for growing self-organizing organoids, tissue culture has come full circle. But close attention to variability and the development and use of quantitative methods to characterize these structures will be necessary if organoids are to fulfill their potential as ex vivo systems for the study of cellular and developmental processes.
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de Souza, N. Organoid culture. Nat Methods 14, 35 (2017). https://doi.org/10.1038/nmeth.4122
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