Karolinska Institute. Sweden: Using a process known as single cell sequencing,
scientists at Karolinska Institutet have produced a detailed map of
cortical cell types and the genes active within them. The study, which
is published in the journal
Science,
marks the first time this method of analysis has been used on such a
large scale on such complex tissue. The team studied over three
thousand cells, one at a time, and even managed to identify a number of
hitherto unknown types.
“If you compare the brain to a fruit
salad, you could say that previous methods were like running the fruit
through a blender and seeing what colour juice you got from different
parts of the brain,” says
Sten Linnarsson
, senior researcher at the
Department of Medical Biochemistry and Biophysics
. “But in recent years we’ve developed much more sensitive methods
of analysis that allow us to see which genes are active in individual
cells. This is like taking pieces of the fruit salad, examining them one
by one and then sorting them into piles to see how many different kinds
of fruit it contains, what they’re made up of and how they
interrelate.”
The knowledge that all living organisms are built up of cells is almost 200 years old. Since the
discovery was made by a group of 19th century German scientists
, we have also learnt that the nature of a particular body tissue is
determined by its constituent cells, which are, in turn, determined by
which genes are active in their DNA. However, little is still known
about how this happens in detail, especially as regards the brain, the
body’s most complex organ.
In the present study, the scientists used large-scale
single-cell analysis to answer some of these questions. By studying over
three thousand cells from the cerebral cortex in mice, one at a time
and in detail, and comparing which of the 20,000 genes were active in
each one, they were able to sort the cells into virtual piles. They
identified 47 different kinds of cell, including a large proportion of
specialised neurons, some blood vessel cells and glial cells, which take
care of waste products, protect against infection and supply nerve
cells with nutrients.
With the help of this detailed map, the scientists were able to
identify hitherto unknown cell types, including a nerve cell in the
most superficial cortical layer, and six different types of
oligodendrocyte, which are cells that form the electrically insulating
myelin sheath around the nerve cells. The new knowledge the project has
generated can shed more light on diseases that affect the myelin, such
as multiple sclerosis (MS).
“We could also confirm previous findings, such as that the
pyramidal cells of the cerebral cortex are functionally organised in
layers,” says
Jens Hjerling-Leffler
, who co-led the study with Dr Linnarsson. “But above all, we have
created a much more detailed map of the cells of the brain that
describes each cell type in detail and shows which genes are active in
it. This gives science a new tool for studying these cell types in
disease models and helps us to understand better how brain cell respond
to disease and injury.”
There are estimated to be 100 million cells in a mouse brain,
and 65 billion in a human brain. Nerve cells are approximately 20
micrometres in diameter, glial cells about 10 micrometres. A micrometre
is equivalent to a thousandth of a millimetre.
The study was carried out by Sten Linnarsson’s and Jens
Hjerling-Leffler’s research groups at the Department of
MedicalBbiochemistry and Biophysics, in particular by Amit Zeisel and
Ana Muños Manchado. It also involved researchers from Karolinska
Institutet’s Department of Oncology-Pathology, and Uppsala University.
The study was financed with grants from several bodies,
including the European Research Council, the Swedish Research Council,
the Swedish Cancer Society, the EU’s Seventh Framework Programme, the
Swedish Society of Medicine, the Swedish Brain Fund, Karolinska
Institutet’s strategic programme for neuroscience (StratNeuro), the
Human Frontier Science Program, the Åke Wiberg Foundation and the Clas
Groschinsky Memorial Fund.
Publication:
‘Cell types in the mouse cortex and hippocampus
revealed by single-cell RNA-seq’, Amit Zeisel, Ana B. Muñoz Manchado,
Simone Codeluppi, Peter Lönnerberg, Gioele La Manno, Anna Juréus, Sueli
Marques, Hermany Munguba, Liqun He, Christer Betsholtz, Charlotte Rolny,
Gonçalo Castelo-Branco, Jens Hjerling-Leffler, and Sten Linnarsson,
Science
online 19th February 2015.