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A Report on a recent Discussion
Meeting of the Royal Society, UK
Margaret A Hughes
The Royal Society, which was founded in 1660, is the UK
national academy of science. It seeks to further the rôle of science,
engineering and technology by offering an active communications programme,
maintaining archives, publishing journals, and funding research. It was
a privilege to attend the recent Discussion Meeting of the Royal Society
held on 24 and 25 September 2003, which was organised by Prof Jeremy Brockes,
FRS of University College, London, and Prof Paul Martin, now at Bristol.
The above image illustrates some of the animals whose abilities to repair
and regenerate were under consideration at the meeting. The organisers
thank Dr Anoop Kumar for help in assembling the image.
The presentations given were based on many years of research by large
and small groups from many centres, with sessions chaired by Prof Paul
Martin, Prof Jeremy Brockes and Dr Fiona Watt.
Invited speakers were:
Professor Jonathan Slack, University of Bath, UK, on:
Cell lineage and cell signalling in Xenopus tail regeneration
Professor Sabine Werner, ETH, Zurich, Switzerland, on:
Fibroblast growth factors in epithelial repair and cytoprotection.
Professor Alejandro Sánchez Alvarado, University
of Utah, USA, on: Functional studies of regeneration in the planarian
Schmittea mediterranea.
Professor Jeremy Brockes, University College London,
UK, on: Plasticity of cell differentiation during lens and limb regeneration
in urodele amphibians.
Professor Paul Martin, now at University of Bristol,
on: Wound Healing and morphogenesis in embryos.
Professor Ellen Heber-Katz, Wistart Institute, Philadelphia,
USA, on: The scarless heart in the MRL mouse.
Professor Mark Keating, Harvard Medical School, Boston,
USA, on: Cardiac regeneration in the zebrafish.
Professor Malcolm Maden, Kings College, London, UK, on:
Retinoic acid is a regeneration-inducing molecule for the adult mouse
lung.
Professor Yann Barrandon, University of Lausanne, Switzerland,
on: Multipotent stem cells and renewal of hair follicles.
Professor Michelle de Luca, Ospedale Civile di Venezia,
Italy, on: Keratinocyte stem cells and tissue engin-eering.
Dr Joanna Price, Royal Veterinary College, London, on:
Exploring the mechanisms regulating regeneration of the deer antler.
Professor Evan Snyder, Burnham Institute, San Diego,
USA, on: Neural stem cells: developmental insights may suggest therapeutic
options.
Professor Mark Ferguson, University of Manchester, UK, on: Scar
free healing: from embryonic mechanisms to adult therapeutic intervention.
Professor Ron McKay, NINDS/NIH, Bethesda, USA, on: From
stem cells to synapses i the central nervous system.
Prof Alvarado pointed out that tissue replacement is broadly
distributed among multicellular life forms and therefore key insights
into mechanisms of regeneration can be gained from studying simpler animals.
Thus research described in this meeting had investigated several animals
as shown in the picture: tadpoles which regenerate tails; planarians which
regenerate from very small segments; newts which can regenerate ocular
tissue, limbs, lips and part of the heart; the adult MRL mouse which can
regenerate cartilage and heart; zebrafish which can regenerate fins, spinal
cord and retina; lung alveoli which can be induced by retinoic acid to
regenerate in the adult mouse; vibrissae follicles in rodents; antler
regeneration in red deer; neural regeneration in the rat. A whole variety
of techniques had been used to study these processes and mechanisms and
we were led through some of the complexities of the molecular biology.
Both embryonic and various adult stem cell populations had been used in
the reported studies.
A number of groups reported on studies to determine the precise location
of stem cells in various tissues or to investigate the processes of dedifferentiation
or transdif-ferentiation of such cells. For example, Prof Barrandon described
studies of vibrissae, locating the hair follicle stem cells to the bulge
region, although these cells can migrate while still remaining multipotent
stem cells and can regenerate all the cell types of hair, sebaceous gland
and epidermis. Prof de Luca identified stem cells in the basal layer of
the limbus region of the eye which can be expanded and preserved by culture
on a fibrin substrate. Prof Jeremy Brockes reported that it is the pigment
cells on the dorsal margin of iris that transdifferentiate to regenerate
lens tissue in the newt. Prof Slack reported that regeneration of the
tadpole tail occurs without de-differentiation or metaplasia. The spinal
cord, notochord and muscle all regenerate from the corresponding tissue
in the stump. They also identified the time frame for amputation in which
regeneration would or would not occur and used transgenic methods to identify
some of the signalling pathways involved.
The rôle of the micro-environment, or sometimes of a specific molecule,
in triggering the differentiation or regenerative process was also described.
For example the regeneration of the lens in the newt appears to be thrombin-dependent.
Prof Maden explained that, in the adult mouse lung, degenerate alveoli
can be induced to regenerate by retinoic acid. This leads to the exciting
possibility that a simple compound could be used to treat diseases such
as emphysema and chronic obstructive pulmonary disease, predicted to become
third commonest cause of death in world by 2020. Retinoic acid is also
expressed in certain regions of the deer antler, but Dr Joanna Price described
how testosterone, insulin growth factor-1 and parathyroid hormone-related
peptide are also key molecules for antler regeneration. The role of elastin
in the regulation of arterial development was considered by Prof Keating.
Prof Barrandon stated that stem cells from all layered epithelia can make
hair follicles if placed in the right environment.
Prof Werner described research on keratinocytes growth factor (FGF-7),
the genes it regulates and its cytoprotection against the toxic effect
of reactive oxygen species on epithelial cells. Therapeutic concentrations
have been identified for protection against some of the side effects of
radiotherapy and chemotherapy such as oral mucositis.
Two presentations focused on neural stem cells (NSC). Prof Snyder showed
how studies culminating in the transplantation of a scaffold containing
neural stem cells to rats following spinal cord injury led to significantly
improved hind limb function. This was believed to be partly due to the
induction of axonal regeneration in the host animals. Prof McKay reported
that multipotential neural stem cells have been isolated from both the
foetal and adult CNS. When expanded in culture and transplanted to rat
brains these cells formed neurons which interacted with astrocytes to
form functional synapses. The results from these studies confirm the potential
for the use of NSCs for the treatment of Parkinson’s disease, stroke,
degeneration due to ageing and other diseases as well as traumatic injuries.
Even when injury is repaired, either by itself or by grafting, one of
the great problems in man is scarring which can lead to loss of function.
This is most obvious in the skin, but is also of great concern in other
organs such as the heart. Paul Martin described the investigation of both
wild type and mutant Drosophila embryos and mechanisms of zippering wounds
together at a stage earlier than inflammatory cells are found. It was
suggested that modifying the recruitment of inflammatory cells could have
potential for reducing scarring. Cardiac injury also leads to scarring
in mammals, but not in amphibians. Prof Mark Keating’s group had
shown that after 20% ventricular resection in zebrafish, a scarless heart
was fully regenerate in two months and they were investigating mechanisms.
The MRL mouse is able to regenerate a number of different tissues, including
the myocardium. Prof Heber Katz described studies showing that, even after
severe ventricular cryo-injury, there was complete regeneration of the
heart in 60 days without any scarring. They were investigating the role
of metalloproteinases and other molecules in this process.
Another area where scarring has horrific consequences is that of the eye
following chemical or traumatic injury. Prof de Luca described exciting
research that has already reached the stage of therapeutic use. Particularly
striking were the results presented on the culture of cells from biopsies
of the limbus of the contralateral eye and their use on a fibrin substrate
to transplant to the eye scarred by a chemical burn. Cell grafts combined
with keratoplasty have led to complete and stable recovery of sight in
67 patients out of 83 treated to date. (Preliminary results for the first
eighteen patients were published in Transplantation in 2001). One case
of bilateral eye injury has now been treated with allogeneic stem cells
from a limbus biopsy from the sister and after two years follow-up the
vision is 10/10 and is stable.
Other instances of current clinical trials were reported. Prof Ferguson
described something of the role of TGFb3, expressed by both fibroblasts
and keratinocytes, in scarless foetal healing and this has now gone into
clinical trials for the treatment of scarring. Three other drugs developed
by RENOVO for scar prevention/treatment have also gone into trial. Junctional
epidermolysis bullosa is a group of severe inherited skin diseases which
results in blistering due to lack of epidermal-dermal adhesion because
of laminin-5 deficiency. Prof de Luca described the procedure of keratinocyte-mediated
gene therapy (transferring the gene into epidermal stem cells cultured
from the patient) which is starting Phase I/II clinical trials with selected
patients.
This was posted as a Discussion Meeting and the fact that all the speakers
kept very well to time meant that the full fifteen minutes allowed for
discussion after each presentation were available and there was no lack
of valuable questions and comments. The last session of the meeting was
a panel (Professors Alvarado, Ferguson and McKay) and open discussion
on the prospects for human regeneration, including the ethical aspects
which are different in various countries. One question that arose was
how available some of the therapies would become to other people. Prof
de Luca, for example, answered that they plan to train ophthalmologists
in other centres in Italy and then to extend their techniques world-wide.
There were 190 participants in this meeting. News of further Discussion
meetings and other activities of the Royal Society can be obtained from
its website www.royalsoc.ac.uk.
Proceedings and written questions and answers will be published in March
or April 2004.
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