NIH. US: A
team in Boston figured out how to transform human embryonic stem cells
and human-induced pluripotent stem cells (created from reprogrammed skin
cells) into insulin-producing beta cells, a potentially major advance
for people with diabetes. Not only did the cells look like healthy beta
cells, they functioned like them in a mouse model of type 1 diabetes,
restoring abnormal blood glucose levels to normal.
Before these cells can be transplanted into patients, however,
researchers need to reproduce the results and extend them to humans.
Another challenge for using these cells to create an “artificial
pancreas” to treat diabetes? Finding a way to shield the
insulin-producing beta cells from the unwanted “friendly fire” of the
immune systems of people with type 1 diabetes.
For most of the estimated 1 to 3 million Americans living with type 1
diabetes, every day brings multiple fingerpricks to manage their blood
glucose levels with replacement insulin [1,2]. The reason is that their
own immune systems have somehow engaged in friendly fire on small, but
vital, clusters of cells in the pancreas known as the islets—which
harbor the so-called “beta cells” that make insulin. So, it’s no
surprise that researchers seeking ways to help people with type 1
diabetes have spent decades trying a find a reliable way to replace
these islets.
Islet replacement has proven to be an extremely difficult research
challenge for a variety of reasons, but exciting opportunities are now
on the horizon. Notably, a team of researchers, led by Douglas Melton of
Harvard University, Cambridge, MA, and partially funded by NIH,
reported groundbreaking success just last week in spurring a human
embryonic stem cell (hESC) line and two human-induced pluripotent stem
(iPS) cell lines to differentiate into the crucial, insulin-producing
beta cells. Not only did cells generated from all three of these lines
look like human pancreatic beta cells, they functioned like bona fide,
glucose-responsive beta cells in a mouse model of type 1 diabetes [3].
Creating a stockpile of insulin-secreting
beta cells has been a longstanding need for many areas of diabetes
research, particularly for the still-experimental field of islet
transplantation. Currently, such transplants are performed using
pancreatic cells harvested from deceased donors (a procedure somewhat
akin to heart, liver, or other transplants). Despite some reports of
islet transplantation curing type 1 diabetes for five years or more, one
major obstacle on the road to wider clinical use is the extremely
limited supply of transplantable islets.
Fifteen years ago, one intriguing possibility for meeting this supply
problem emerged when basic scientists isolated the first hESCs. Like
gardeners learning to germinate a new type of seed, researchers
worldwide began tinkering with which growth-inducing factors to add,
when, and in which sequence, to prompt these undifferentiated stem cells
to commit to becoming specialized adult cells. Successes began to
appear for cardiac cells, neurons, smooth muscle cells, and other cell
types, but beta cells proved to be extremely challenging. Furthermore,
just a few cells wouldn’t do: to be useful, the protocol would have to
produce a vast, renewable source of functional beta cells for
transplantation. And what a vast source that would have to be! It takes
anywhere from 340 million to 750 million beta cells to provide treatment
for type 1 diabetes in just one 150-pound person.
What’s particularly encouraging about the latest findings is they
suggest a way forward for solving the supply problem. After years of
trial and error, Melton and his colleagues have developed a rigorous
recipe of adding and subtracting natural biological factors to coax stem
cell lines into becoming functional, insulin-secreting pancreatic beta
cells. Within a matter of a few weeks, this approach can reliably
produce 300 million beta cells in a single 500 milliliter flask—with
researchers estimating that one or two flasks of such cells would be
enough to treat a patient. If these results, which were published in the
journal Cell, can be reproduced and extended to humans, the
ability to generate an ample supply of fully functional,
insulin-producing beta cells may finally be within our reach.
Melton’s team has not been alone in this multiyear effort—many other
researchers in the public and private sectors have been hard at work
developing potential stem-cell therapies for type 1 diabetes and other
diseases. However, I was especially pleased to learn that the hESC line
used in their work (HUES8) was among the first lines approved by NIH in
response to a 2009 Executive Order enabling more hESC lines to be added
to the list of those approved for federally funded research. In
accordance with NIH guidelines, HUES8 was derived from embryos that were
donated under ethically sound informed consent processes. The other
cell lines used in this study are induced pluripotent stem (iPS) cell
lines, which are reprogrammed adult skin or blood cells with the ability
to differentiate into heart, nerve, muscle, and many other kinds of
cells. iPS cell technology builds upon the Nobel Prize-winning work of
Japan’s Shinya Yamanaka, and iPS cells have the particularly appealing
feature of being obtainable from anyone, meaning a supply of iPS-derived
beta cells could be potentially produced and reinfused without risk of
transplant rejection.
For all who have type 1 diabetes or children with the disease (and
Melton has two!), the most recent stem cell research accomplishment,
while exciting, is still incomplete until it makes a real difference in
patients’ lives. To that end, Melton and his colleagues are now
collaborating to develop an implantable micro-device, about the size of a
credit card, that will shield transplants of insulin-producing beta
cells from that unwanted friendly fire of the immune system—another
major hurdle that must be cleared in order for such treatment approaches
to become commonplace [4]. If researchers succeed in developing this
and other next-generation treatments, we’d certainly have cause to
celebrate—not only because of the excellent science but, most of all,
the improved quality of life and potential longer term survival for
those who live each day with type 1 diabetes.
References:
[1] Foundational Data Report: The Size of the Population Impacted by Type 1 Diabetes. Juvenile Diabetes Cure Alliance, 2013.
[2] National Diabetes Statistics Report, 2014. Centers for Disease Control and Prevention.
[3] Generation of Functional Human Pancreatic β Cells In Vitro. Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA. Cell. 2014 Oct 9;159(2):428-39.
[4] Stem-cell Success Poses Immunity Challenge for Diabetes. Ledford H. Nature 2014. Oct 14.