In 2009, biochemists Hans Clevers and Toshiro Sato created the world’s first true organoid—a clump of cells mimicking the gut of a mouse. In the ensuing years, scientists have developed a variety of these lab-grown organs to test therapies, investigate embryonic development, and to play the video game Pong. In only 16 years, organoid technology progressed to such an extent that experts began pondering the ethics of organoids, even worrying that they might one day accidentally create something with a degree of consciousness.
Now, a new study published in the journal Nature details another big development in the world of lab-grown brains. A team of researchers at the Institute of Science and Technology Austria (ISTA) successfully grew a cerebral cortex from the stem cells of mice. As is the case with most organoids, scientists created the structure using pluripotent stem cells—specifically, mouse embryonic stem cells capable of differentiating into a range of cell types, including the neurons and glial cells that make up the cortex. The ultimate goal of this mini-mouse brain is to understand brain development and to study disorders triggered by developmental mishaps.
“In our lab, we study how the brain develops from stem cells,” ISTA’s Simon Hippenmeyer, senior author of the study, said in a press statement. “How a brain reaches the right size, how stem cells know when and into which neurons they should develop, but also what happens when something goes wrong during development or disease—for example, in microcephaly or macrocephaly, where the brain is unusually small or large.” After developing a stable mouse stem line, the team compared specific developmental stages between the mouse organoid and the real thing. Using single-cell sequencing, they tracked which cell types emerged in each system, their relative abundance, and their timing. Separately, they used Mosaic Analysis with Double Markers (MADM)—a genetic technique that labels a single stem cell and all of its descendants with a distinct color—to trace how one stem cell divided and multiplied over time in both the living mouse brain and the organoid. Prior MADM studies had already mapped a clear, linear roadmap of cortical development in living mice. Applying the same technique to the organoid allowed researchers to directly compare the two step by step. The comparison revealed a mixed picture. The organoid largely produced the right cast of cells, but without the strict order and timing of a living brain’s development. Something was missing that couldn’t be explained by the stem cells’ behavior alone. “The physical force of self-organization alone is apparently not enough,” Hippenmeyer said in a press statement. “Factors present in in-vivo systems are missing—the so-called stem-cell niche.”
A stem cell niche is everything except the stem cell—the microenvironment of nearby cells, blood vessels, signaling molecules, growth factors, and mechanical signals that regulate stem cells. Within a mouse, this microenvironment creates linear brain development: stem cells multiply, asymmetric division produces neurons, and then glial cells arrive on the scene. In organoids, this process is a bit messier, although glial cells did emerge at the correct time. (Yahoo News)
