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Retinal Progenitor Cells in Regeneration and Repair Highlight New Therapeutic Targets
transplants. Survival of cells transplanted into the subretinal space is progenitor cell division, migration, differentiation and, ultimately,
now accepted.
65
More recently, electrophysiological and behavioural functional integration.
evidence has been presented of functional integration of these
transplants in mice with inherited retinal degeneration;
66
therefore, Towards Therapy – The Caveats
cellular transplantation in the retina is clearly possible. It is a question In the study of tissue repair and regeneration, cell lines offer some
of identifying the correct cell to transplant in sufficient numbers to advantages, with cells being available in large numbers, cells
justify the surgical trauma involved. To be effective we need to better having reproducible properties and reduced numbers of unwanted
understand the nature and behaviour of intrinsic cells and find cells cell types compared with primary cell cultures. However, with
that integrate safely and in sufficient numbers and generate the respect to therapy, the accumulation of karyotypic abnormalities
appropriate lineage. Cells will integrate into a tissue if the right cell is and certain mutations
70
in embryonic stem cells cultured in vitro
generated in an environment where there is a need, such that the after more than 20 passages
71
is of concern and correlates with a
tissue can accept the integrating cells.
25,67
Transplantation requires an loss of toti-potency,
71
which needs to be refined before therapy can
understanding of cell biology, the isolation of cells able to integrate be considered. Similar concerns arise for tissue-specific cell lines
into the retina and the extra- and intra-cellular signalling that guides (e.g. Müller cells),
72
where cells become near-triploid.
73
Transplanted
these events. There is a need to study single cells (from developing primary cells and in situ progenitor populations are important new
therapeutic targets for optimising repair and regeneration in the
retina, for example via gene therapy. In this respect it is
The treatment of diseases with
encouraging that human embyonic stem cells reliably generate
destruction of tissue architecture
RPCs,
74
making them useful for screening primary cell interventions.
Although primary cells from post mortem retina are subject to
represents a special challenge as cellular
variations in tissue
2
and adult human cells in culture show slow
replacement may require accompanying
growth
1,2
compared with immature retinal cells
50
and animal cells,
4,5
adult human retinal progenitors are a target for human therapy and
tissue synthesiser technology if it is to
a possible source of the retina’s inherent regenerative potential.
lead to functional recovery.
The treatment of diseases with destruction of tissue architecture
(see Figure 1) represents a special challenge as cellular
tissue); where this has been possible, gene expression is replacement may require accompanying tissue synthesiser
heterogenous
20
due to the cells studied being at different stages of technology if it is to lead to functional recovery. The understanding
the cell cycle, as well as RPCs using different genes to exit the cell of retinal cell biology in health and disease from all of these areas
cycle.
20
This suggests that cell fate and lineage decisions are made of research combined with advances in gene therapy offers a future
early in cellular differentiation – before cells have ceased dividing – as with realistic hope of treating what is currently considered to be
by definition all RPCs in this study were identified as expressing cyclin untreatable blindness. n
D1.
20
Importantly, RPCs are not a single cell type but rather a variety of
cells at various stages along several as yet incompletely
Eric J Mayer is a Consultant Senior Lecturer at the
characterised differentiation pathways. Comparing the transcriptional
University of Bristol and a National Career Scientist
profiles of retinal progenitors between adult and developing tissue Award Holder from the UK Department of Health
will establish whether adult progenitors mirror those in development.
Research and Development. His research and
publications focus on retinal cell biology, central
For example, transcriptomics will predict and focus therapies.
nervous system repair and regeneration,
stem/progenitor cells and clinical medical and surgical
Do Cellular Interactions Influence
retinal disease. He is a Fellow of the Royal College of
Progenitor Cell Fate?
Ophthalmologists and a Member of the British and Eire
Association of Vitreo-Retinal Surgeons and Oxford Congress of Ophthalmology. Dr
Functions such as vision are testimony to the interaction of cells. Of Mayer serves as an Examiner for the International Council of Ophthalmology.
critical importance in this respect is the interaction of RPCs with
microglia. RPCs are key to the retina’s potential for cellular
Andrew D Dick is Chair and Head of the Academic Unit
of Ophthalmology and Head of Research for Clinical
replacement, and microglial cells are central to regulating the
Sciences at the University of Bristol. His research
response of tissues to various diseases. Microglia express CD200R interests include immunobiology of inflammation of the
and other inhibitory receptors that control activation status, with its
eye, identifying targets for immune intervention and
how the retina responds to inflammation and injury and
ligand expressed on the retinal neurone CD200.
68,69
Despite this
interaction with retinal progenitor cell turnover and
cognate receptor control, signals (such as interferon-gamma) will tissue repair. He has served as UK Editor of the British
promote classic macrophage activation of microglial cells, with
Journal of Ophthalmology. Dr Dick is Director of
Research for the UK National Eye Research Centre and sits on numerous Editorial
subsequent release of pro-inflammatory cytokines, growth factors
Boards of international journals. He was recently awarded Fellowship of the UK
and proteases and increased cell migration (see Figure 5). IL-6 directly Academy of Medical Sciences.
inhibits neurosphere formation in vitro and thus has potential for
1. Mayer EJ, Carter DA, Ren Y, et al., Neural progenitor cells neurospheres from adult human retina, Br J Ophthalmol, 4. Tropepe V, Coles BL, Chiasson BJ, et al., Retinal stem cells
from post-mortem adult human retina, Br J Ophthalmol, 2007;91:1216–18. in the adult mammalian eye, Science, 2000;287:2032–6.
2005;89:102–6. 3. Turner DL, Cepko CL, A common progenitor for neurons 5. Ahmad I, Dooley CM, Thoreson WB, et al., In vitro analysis
2. Carter DA, Mayer EJ, Dick AD, The effect of post-mortem and glia persists in rat retina late in development, Nature, of a mammalian retinal progenitor that gives rise to
time, donor age and sex on the generation of 1987;328:131–6. neurons and glia, Brain Res, 1999;831:1–10.
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