So stem cells have inspired a variety
of scientists and humans for their possibility to regenerate tissues and to
help with wound healing in quite a … fashion and even though in
preclinical data they have generated good results, it transfers to the clinic
in different diseases, in particular in non healing wounds is still lacking. And
this is mainly due to the fact that for example, mesenchymal stem cells, they
cannot be quite reliably isolated. More recently, single cell
surface molecules, the ABCB5 transporter, has been identified in a newly
characterized mesenchymal stem cell or mesenchymal stromal cell. And we had
the chance to help with his characterization. And I think this may be
at least a preclinical breakthrough and is on its way to the clinic in a phase 2 study with very convincing results, even though in little numbers of
patients. So what have we found? More recently, we found that stem cells are
like adaptive drug stores. So they can sense a micro environment of different
wound conditions, and they can exactly shape answer with the release of
different molecules, which help a wound to heal. Why is it important? Because it
is very important that wound undergoes different phases and if you inject just
a growth factor which has been done previously, you can never sense if it is enough, if it is not enough or what comes next. The mesenchymal stem cells can do this. So we had been interested for quite a while in non-healing wound chronic venous leg ulcers. And these ulcers, they are due to
a … insufficiency and a lot of pressure is in the veins of the lower
limb. And this results in the fact that red blood cells are pressed through the
veins into the tissue. This drives a terrible inflammation. There is an
unrestrained activation of M1 macrophages and these that we found
drive the whole process. The wound cannot progress through the different
phases and stages of wound healing, the wound does not heal. That is bad and
there is no real cure. Certainly you can operate and you should operate the
venous … insufficiency. But there is currently not a good cure, and therefore
we set out how we can use or employ mesenchymal stem cells to bring down
the unrestrained activation of M1 macrophages. And the beauty we had
a couple of years ago was that there was a researcher who found ABCB5 to be
selectively expressed on mesenchymal stem cells under certain conditions. And
with this you can purify under GMP condition. This has been done by … Those amesenchymal stem cells from the skin expanded. What we did is we characterized these cells. They are really stem cells, even if you have them
in culture after a couple of weeks, they still express mesenchymal as well as
stem cell markers. They have the potential of tree lineage differentiation, so they
can undergo adipogenic, osteogenic, dermogenic and also chondrogenic
differentiation. And they have self renewal capacities, that is the
characteristic of stem cells. With these cells we have done experiments in
a model previously developed by us, it’s a model with mice where mice are overloaded with
iron.This is a characteristic of chronic venous leg ulcers in humans, they all
have this brownish skin, as a matter of iron accumulation. So we set up this
mouse model. This mouse model completely reframed what we have observed in human chronic venous leg ulcers with an unrestrained activation of M1 cells. And
when injecting those viable human cells, so it’s you know transplant, the mice
healed much better, significantly better, and when studying different
wound phases, we could show that first M1 macrophages undergo a switch to M2
macrophages, the release of effector molecules like tumor necrosis factor
alpha interleukin 12 is reduced and M2 macrophages, regenerative cytokines of
regenerative M2 macrophages are released much more. You have an enhanced re-epithelialization over the wounds, iron overload wounds, you have a contraction
of the wounds and it heals much better. That was exciting, and in particular as we could show that these cells, human cells, did not survive longer
than three days in a mouse, that is what we want, we don’t want an engraftment. But
we wanted the sensing of this hostile micro environment of chronic wounds and we really wished to exploit this and finally we identified the molecule which
is released from injected mesenchymal stem cells ,ABCB5 positive mesenchymal stem cells. It is interleukin 1 receptor antagonist, and that makes a
whole lot of sense because in chronic venous leg ulcers and in iron overload
marine wounds, you have a lot of IL-1 alpha and beta and TNF alpha. If you can
disrupt these poor inflammatory cytokines, then the whole vicious cycle of self perpetration is interrupted. The amazing thing is that the M2 macrophage came out. So what we have
here, we have a cell which do not engraft and which obviously, by the release of
paracrine factors can fully redirect non-healing wound to a healing situation.
And this company has done bio distribution and safety studies and they
are published now in psychotherapy and MIT center study, phase two study has
been set up for chronic venous leg ulcers and certainly another person is
coordinating it, because I’m more in the pre clinic but our clinic is also
recently contributing. And they have shown and also released the first twenty
patients. I have seen them. And there is no one which completely failed. They have different healing rates, it is clear, we are all individuals. But there is no one
who distinctly fails and you have to consider there is a fraction of chronic
venous leg ulcers which do not heal even if you have compression stockings or did
everything, the tissue is so much switch to a hostile micro environment they do
not heal. So even though as a scientist we have to wait for the full data set
and possibly for repetitive study with high numbers. But I’m quite excited and
I’m convinced that good science really drives good products.