At the crossroad of developmental biology and tissue engineering, there is a group of scientists trying to delicately coax stem cells down a specific path. In the metaphoric sense, they are most interested in how the nature of their cells evolves over time.
But what if stem cells could teach us something about evolution itself? You know, the Darwin and finches kind?
One of the many unresolved puzzles in comparative neurobiology is why different species have brains of varying sizes/cortical neuron density. It is thought that these factors influence cognitive ability, but we don’t yet understand what determines these alternate anatomical fates.
This question is perhaps most interesting when comparing species that are relatively close on the phylogenetic tree. For example, why are human brains different from those of other primate species? Most of what we know about mammalian corticogenesis (the development of the cerebral cortex) comes from rodent models, which, as you can imagine, has many limitations.
To tackle this problem, Frederick Livesey’s group, at the University of Cambridge, has taken a stem cell-based approach, using species-specific pluripotent stem cells (PSCs) to compare corticogenesis of humans, chimpanzees, and macaques in vitro. These latter two primates have, respectively, <50% and 10% of the number of neurons as humans, and so one would expect a developmental explanation.
Dr. Livesey’s group used their previously established PSC cortical differentiation protocol to form organoids with diverse neural progenitor (stem) cells in specific spatial arrangements. They could then use fluorescently label specific clones of cells within the organoid to track the proliferative capacity of these cells over time.
A general theme with progenitor cell divisions is that they can divide symmetrically to produce two daughter progenitor cells, asymmetrically to produce one progenitor cell and one mature cell (non-proliferating), or terminally to produce two mature cells. In the context of cortical development, the mature cells are neurons.
Based on their studies, human progenitor cells were found to maintain symmetric division for longer, whereas macaque cells transitioned to forming neurons sooner. Thus, while macaque corticogenesis leads to mature neurons at an earlier time point, because the original pool of progenitor cells did not have the opportunity to expand as long, the total number of neurons ends up being much smaller.
Curiously, when human progenitor cells were transferred to macaque organoids and vice versa, the clones maintained their species-specific proliferation pattern. This indicates that the time frame for cell proliferation is something intrinsic to the cell rather than a result of interactions with neighboring cells.
The main conclusion from the paper is that there is a cell-intrinsic, primate-specific difference in cortical progenitor proliferation, which may partially explain differences in brain size.
A more personal takeaway, however, is a reminder to not limit one’s imagination to trending applications in the stem cell and tissue-engineering fields. Amongst a plethora of studies aimed at using engineered tissues as reparative therapies or disease models, this evolutionary application could be seen as a revolutionary idea.
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