Developmental clocks are crucial to regenerative medicine, since many cell types take long periods to mature, limiting their utility to human therapies.
The mystery of what controls the range of developmental clocks in
mammals - from 22 months for an elephant to 12 days for a opossum -
may lie in the strict time-keeping of pluripotent stem cells for each
‘Stem cell development is a stubborn process not requiring external stimulus from the mother or the uterus to know their pace of development.’
The regenerative biology
team at the Morgridge Institute for Research, led by stem cell pioneer
and UW-Madison professor James Thomson, is studying whether stem cell
differentiation rates can be accelerated in the lab and made available
to patients faster.
In a study published in February online editions of the journal Developmental Biology
Morgridge scientists tested the stringency of the developmental clock
in human stem cells during neural differentiation.
First, they closely
compared the differentiation rates of the cells growing in dishes
compared to the known growth rates of human cells in utero. Second, they
grew the human stem cells within a mouse host, surrounded by factors -
such as blood, growth hormones and signaling molecules - endemic to a
species that grows much more rapidly than humans.
In both cases - lab dish or different species - the cells did not
waver from their innate timetable for development, without regard to
"What we found remarkable was this very intrinsic process within
cells," says lead author Chris Barry, a Morgridge assistant scientist.
"They have self-coding clocks that do not require outside stimulus from
the mother or the uterus or even neighboring cells to know their pace of
While the study suggests that cellular timing is a stubborn process,
the Thomson lab is exploring a variety of follow-up studies on
potential factors that could help cells alter their pace, Barry says.
One aspect of the study that's immediately valuable across biology
is the realization that how stem cells behave in the dish aligns almost
precisely with what happens in nature.
"The promising thing is that we can take species of stem cells, put
them in tissue culture, and more confidently believe that events we're
seeing are probably happening in the wild as well," Barry says. "That is
potentially great news for studying embryology in general,
understanding what's going on in the womb and disease modeling for when
things can go wrong."
It also opens up potential avenues in embryology that would have
been inconceivable otherwise - for example, using stem cells to
accurately study the embryology of whales and other species with much
longer (or shorter) gestation rates than humans.
In order to accurately compare development timing across species
with wildly different gestation rates - nine months compared to three
weeks - the team used an algorithm called Dynamic Time Warping,
originally developed for speech pattern recognition. This algorithm will
stretch or compress the time frame of one species to match up with
similar gene expression patterns in the other. Using this process, they
identified more than 3,000 genes that regulate more rapidly in mice and
found none that regulate faster in human cells.
The impact of solving the cell timing puzzle could be enormous,
Barry says. For example, cells of the central nervous system take months
to develop to a functional state, far too long to make them
therapeutically practical. If scientists can shorten that timing to
weeks, cells could potentially be grown from individual patients that
could counteract grave diseases such as Parkinson's, Multiple Sclerosis,
Alzheimer's, Huntington's disease and spinal cord injuries.
"If it turns out these clocks are universal across different cell
types," says Barry, "you are looking at broad-spectrum impact across