Seeing in 3D

We've all heard the stories about Archimedes taking a bath, Newton
sitting under an apple tree - about moments when the secrets of nature suddenly
revealed themselves to humankind. Well, stem cell science and regenerative
medicine are nothing like that!

Every success is built on years and years of painstaking research,
on numerous small but important steps, each essential for us to move forward. A
paper in Nature Biotechnology from Professor Robin Ali and groups at University
College London, Institute of Ophthalmology and Moorfields Eye Hospital, is one such
step.

It was not a spur of the moment development; it was built on Professor
Ali's previous work and on a new laboratory technique of three-dimensional (3D)
culture developed by Dr Yoshiki Sasai at the RIKEN Center for Developmental
Biology in Japan. Protocols involving pluripotent stem cells, both embryonic and induced, had already been developed, but no-one had
successfully used stem cells as a source of photoreceptor cells suitable for
retinal transplantation. This study did it for the first time.

Would results of this study return eyesight to the blind? Sadly not, so
why did this make such a big news splash? The study is an important milestone. Professor
Ali and his team realised a while ago that a traditional 2D cell culture system
is not capable of providing the right environment for differentiation of
pluripotent stem cells into photoreceptor precursors. There was something
missing.

They hoped that they might circumvent the problem if they were able
to copy the microenvironment of embryonic tissue during development. Work
from Dr Sasai's lab suggested that introducing 3D cell culture was the best way
to go. And indeed it was. Retinal progenitor cells generated in the 3D system
were capable of differentiation into mature retinal cell types. Moreover, these
cells were able to integrate with the mouse retina. The transplanted cells,
made distinguishable through expression of green fluorescent protein, were
detected during follow-up six weeks after transplantation.

The study has broader implications than the step toward restoration
of vision through transplantation of photoreceptors. It points out how
important it is to mimic closely the natural microenvironment.

It has been known for many years that culturing embryos under
physiological oxygen levels yields much better results than culturing them at
normal atmospheric levels. For dermatologists building a 3D epidermis, only
exposure of the skin cells to atmospheric air will result in the proper
stratification of epidermis. A couple of weeks ago, scientists in Japan grew
functional liver buds in vitro (see BioNews 712). They mixed together hepatocyte progenitors
derived from human pluripotent stem cells, human umbilical vein endothelial
cells and human mesenchymal cells - three cell types normally present in the liver
— and cultured them together. The results were astonishing; the researchers were
able to rescue animal models of liver failure by transplanting such off-the-shelf
liver buds. Dr Hideki Taniguchi, who led the team, shared the same vision as Robin
Ali: mimic the natural microenvironment as closely as possible.

But will these moves to mimic
nature usher in a new era of wizardry, where we will be cooking up witches'
brews recipes of dead toads and bats, cell of mesenchyme and tissue of embryo, to
grow a new heart or brain in a dish? No. In order to manipulate a system and
get what we want when we want, we have to learn the molecular mechanisms and
understand the laws of nature.

Just remember, Judah Folkman, the founder of the field of angiogenesis, was the first to note that growth of all malignant tumours is
angiogenesis-dependent. However, the discoveries that originated the concept
and developed the field were not enough to develop the first potent therapeutic
antiangiogenic agent. It is rather Napoleone Ferrara, who identified the human
vascular endothelial growth factor (VEGF) gene and described its proangiogenic
characteristics, who is credited for leading the way to the first
antiangiogenic therapy, bevacizumab (Avastin).

Who will win the race to provide off-shelf
organs or organoids in the field of regenerative medicine? History suggests it won't
be the groups whose work has got us this far, nor those who'll continue the
fine-tuning. So although the work from Professor Ali's group is undeniably a milestone,
there are many more steps to come before this strategy could be used as a cell-based
therapy for particular types of blindness.