For nearly two decades now, developmental biologist Yoshiki Sasai from Japan’s RIKEN Center for Developmental Biology has slaved away to perfect a recipe: the culture medium that could induce mouse embryonic stem cells to form organs with no additional ingredients. Disheartened by his incomplete success in generating brain tissue from stem cells, Sasai began a side project to grow early-stage mouse eyes, because they are “relatively simpler in structure than cortex” tissue, he said.
In his free time, Sasai fussed over his medium, fine-tuning the concentrations of ingredients—adding a gel containing laminin proteins essential for constructing basement membranes, decreasing growth factor levels. With his latest recipe complete, Sasai mixed in mouse embryonic stem cells—and then sat back to see what would happen, if anything.
Like most embryonic cells, aggregates of stem cells first formed hollowed spheres. But after 7 days Sasai and his colleagues noticed some “funny structures” sprouting off the outer fringes of the spheres and glowing green with a marker indicating retinal differentiation, Sasai recalls. Within the next few days each of those small buds folded in upon itself to form a goblet shape with two cell layers: an outer retinal pigment epithelium, which provides nutrients to the visual cells, and an inner layer of retinal neural cells. These structures were optic cups, the precursor to the fully differentiated retina—and they appeared to be forming “hands-off” within Sasai’s culture mixture.
“They captured multiple cell types self-organizing and actually forming a shape which was recognizable to anybody as an eye cup,” says stem cell biologist Bruce Conklin of the Gladstone Institute of Cardiovascular Disease in San Francisco. “Now if you can capture that, you can start taking it apart and seeing what makes it happen.”
Because the eye is one of the first organs to form during embryonic development, it may be easier to culture using basic ingredients, says Conklin. Therefore, Sasai’s brew may not be easily tweakable for studying the development of other organs. But what this research does show is that it is possible to stimulate early organ growth from the right mix of molecules and stem cells alone.
“The main lesson in all of this is to first see what nature can do by itself when given essentially minimum instructions and the proper environment,” says Conklin. “And, given the right environment, the cells will jump into action.”
M. Eiraku et al., “Self-organizing optic-cup morphogenesis in three-dimensional culture,” Nature, 472:51–56, 2011.