February 14, 2019
- Salk scientists have made human and nonhuman primate neural progenitor cells to investigate brain development
- Nonhuman primate neurons mature faster and migrate further than human neurons
- Human neurons develop longer dendrites with greater spine densities
- Findings shed light on brain evolution
Carol Marchetto and colleagues in Professor Rusty Gage’s lab at the Salk Institute, USA, have taken a novel and reproducible approach to investigating the evolution of the brain: by using stem cells.
What makes human brains different from those of other primates?
Previously, the only way to answer this question was to get brain tissue from humans and nonhuman primates and compare. Whilst this is a great way to make direct comparisons between humans and closely-related species, it does not reveal much about the development of differences in brain structure and size, and how these differences have evolved.
Also, obtaining tissue is invasive and normally requires the death of the tissue donor. This is not ideal when you consider that some nonhuman primates are endangered, such as bonobos and chimpanzees (not to mention how relatively rare it is for people to donate their bodies to science).
Primate neural progenitor cell bank
Marchetto et al. harmlessly took skin cells from chimpanzees and bonobos and used stem cell technology to coax them into becoming neural progenitor cells, cells that can grow into any type of brain cell. The group is currently developing a bank of neural progenitor cells from nonhuman primates that they intend to make available to the research community.
“This is a novel strategy to study human evolution,” says Carol Marchetto, a Salk senior staff scientist in the Laboratory of Genetics, co-first author and one of the study’s senior authors.
“We are happy to share these primate cell lines with the scientific community, so that researchers from around the world can examine primate brain development without the use of tissue samples. We anticipate this will lead to numerous new findings over the next few years about the brain’s evolution.”
Exploring developmental differences between human and nonhuman primate neurons
The group measured how these cells matured and migrated in comparison to human neural progenitor cells. They did this in a dish and found that chimpanzee and bonobo neurons went through periods of rapid migration in comparison to human neurons, which were slower to develop.
At the genetic level, the group found 52 genes related to migration that differed in their expression between the species.
Transplanting stem cells to understand brain cell development in vivo
Going a step further the group transplanted a mix of human and chimpanzee neural progenitor cells into mice. They then tracked the cellular development and migration over two weeks. Their findings revealed that chimpanzee cells migrated 3x further than human cells.
To investigate how the cells developed and matured, the scientists tracked cells for up to 19 weeks, investigating the amount of dendrite outgrowth, dendritic spine development and spine density among other factors. They found that overall human neurons grew longer dendrites with greater numbers of spines.
Of most interest was the variability in the rates of maturation between the neurons from the different species. For example, at 4 weeks post-transplant, the neuronal processes of human cells began elongating and continued growing until the last time point captured at 19 weeks, whereas the chimpanzee cell dendrites grew up until 2 weeks, but then stopped growing after this.
Similar variability was observed in spine number. The number of spines counted on dendrites was similar up to 6 weeks before human cells showed rapid increases in spine development at 8 and 19 weeks.
Measuring functional development of primate neurons
Having seen these striking differences in the morphological development in vivo the scientists wanted to understand if there was a functional difference in the maturation of the cells.
Going back to the in vitro approach, the group differentiated neural progenitor cell lines from 4 human, 2 chimpanzee and 2 bonobo individuals. Growing the cells on multi-electrode arrays in a dish they observed differences in electrical activity between the human neuronal cells and the chimpanzee and bonobo neurons. After 2 weeks of neuronal maturation, the chimpanzee and bonobo neurons showed a higher firing rate than human neurons. However, after 6 weeks of maturation, the human neurons had more than 10x times the level of activity.
If only we could have watched it happen in real time
The differences in migration, maturation and functionality seen in this study explain some of the differences in brain organization and development between human and nonhuman primates. This study represents a giant leap forward in comparative neurobiology that will undoubtedly lead to a better understanding of brain development and evolution.
The transplantation of the mixture of human and nonhuman progenitor cells into mice brains was a key experiment, that was hampered by the fact that mice had to be sacrificed at 2, 4, 6, 8 and 19-week time points. Whilst highly informative, the analysis can only provide snapshots of neuronal development at these time points, and cannot capture any changes that may have happened in between.
If in vivo imaging approaches had been employed, it may have been possible to track developmental changes daily over the time period.
Regardless, this study showcases an exciting approach to understanding brain evolution. As senior author and Salk president Professor Rusty Gage said of the study:
“This study provides insights into the developmental organization of the brain and lays the groundwork for further comparative analyses between humans and nonhuman primates.”
Marchetto, M. C., Hrvoj-Mihic, B., Kerman, B. E., Diana, X. Y., Vadodaria, K. C., Linker, S. B., … & Oefner, R. (2019). Species-specific maturation profiles of human, chimpanzee and bonobo neural cells. eLife, 8, e37527.