Pluripotent stem cells in culture will spontaneously differentiate into many cell types if conditions that promote pluripotency are not maintained. But in recent years, researchers have found that under the right conditions, stem cells in culture can also form structures of striking, tissue-like complexity—even reminiscent of what is seen in vivo, at least to a first approximation. Perhaps most surprisingly, once key enabling conditions have been identified, it seems that one need not do very much to the cells to achieve these effects.

Stem cells can organize into tissue-like structures in vitro. Credit: Katie Vicari

For instance, when allowed to form three-dimensional aggregates in Matrigel, mouse and human embryonic stem cell–derived retinal pigment epithelial cells can organize into optic cups and, upon more prolonged suspension culture, into stratified neural retina (Nature 472, 51–56, 2011; Cell Stem Cell 10, 771–785, 2012). More recently, human pluripotent cell–derived neuroectodermal cells embedded in Matrigel and cultured in spinning bioreactors were shown to organize into millimeter-scale organoids containing structures that resemble the immature cerebral cortex, arguably one of the most complex tissues in the human body (Nature 501, 373–379, 2013).

Preceding some of this work on pluripotent stem cells was the demonstration that intestinal stem cells, again under specific culture conditions and embedded in Matrigel, can organize into gut-like organoids that contain all the differentiated cell types present in the in vivo tissue (Nature 459, 262–265, 2009; Nat. Med. 15, 701–706, 2009). Similar observations have been made for both embryonic stem cells differentiating along other lineages and for adult stem cells of other tissues.

We are far from being able to generate organs in vitro at the wave of a wand; the culture well or bioreactor will never fully recapitulate what is going on in the body. Indeed, it is often proposed (and has in some cases been demonstrated) that implant into the in vivo milieu will be required for the final maturation of some cell types derived in vitro.

Nevertheless, as a tractable, accessible system to study normal development and tissue maintenance as well as the diseases that arise when these processes go wrong, stem cell–derived in vitro organoids have tremendous potential.