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Posterior Segment
Retinal Progenitor Cells in Regeneration and Repair
Highlight New Therapeutic Targets
Eric J Mayer, Balini Balasubramaniam, Debra A Carter and Andrew D Dick
Academic Unit of Ophthalmology, University of Bristol
Abstract
The quest to understand the ability of the retina to not only sustain its function throughout life but also, as a result of pathological
degeneration, to promote repair via stimulating endogenous regenerative capacity or via cell replacement is nearing clinical assessment.
However, we still need to understand the kinetics and dynamics of cell replacement in healthy or ageing retina. This would lead to the
possibility of manipulating endogenous ocular progenitor cells towards facilitating cell replacement when degeneration has ensued.
Arguably, the most clinically immediate benefits will arise from cell-based therapies. However, the questions of which cells to use to
maximise clinical outcome – including ocular sources or manipulation of non-ocular cell sources, including embryonic stem cells, as
neuralised progenitor cell sources – and how best to deliver therapy remains unqualified. Ultimate success will depend on integration into
damaged host tissue, prevention of gliosis and knowing which cells to target to replace.
Keywords
Prognitor cells, retina, stem cells
Disclosure: The authors’ research is supported by the National Eye Research Centre, the Guide Dogs for the Blind and the McAlpine Foundation. Balini Balasubramaniam is
supported by the Dr Hans and Mrs Gertrude Hirsch Scholarship. Eric J Mayer is supported by a National Career Scientist Award from the Department of Health and NHS R&D.
The authors have no conflicts of interest to declare.
Acknowledgements: We thank Mr EH Hughes for generating Figure 1 images.
Received: 13 March 2009 Accepted: 30 March 2009
Correspondence: Eric J Mayer or Andrew D Dick, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, UK. E: e.mayer@bristol.ac.uk or a.dick@bristol.ac.uk
Retinal Repair and Regeneration Adult Tissue Progenitor Cells and
Throughout life, tissues and organs constantly repair and replace cells Their Detection
to maintain optimal function. The central nervous system (CNS) – the To maintain tissue and cellular homeostasis and function, cellular
brain, retina and spinal cord – was conventionally thought, because of replacement is likely to be ongoing, inconspicuous and, possibly,
poor response to damage, to have only limited ability to repair; stochastic. It is unlikely to occur more quickly in adults than during
however, even without damage how can a set of neuronal cells last a development. Retinal cell replacement occurs within myeloid cell
lifetime? It is clear that when a tissue is structurally damaged (see populations (where perivascular macrophages and microglia are
Figure 1) there is progressive loss of function over time and recovery replaced over six months),
11
and is likely to be much quicker than
is far more limited. This happens following trauma (surgical or neural cell replacement. Establishing their connections and explaining
accidental) or with certain diseases that mechanistically have in recovery, if present, is a slow process. So, what is the rate of cell
common direct cell death, ischaemia and inflammation (diabetes, replacement in normal retina? While it is possible to see cells dying in
stroke, autoinflammatory disease and degenerative conditions). the retina,
11
the rate of cell loss in the normal retina is difficult to
establish as there is no analogous method for seeing new cells added
Any recovery of function after successful control of ischaemia, in the steady state, unless they are directly labelled and transferred.
12
inflammation or cell death may occur via cell replacement. However, Replacement from in situ mitosis is uncommon as few cells divide in
to this end there remains controversy over whether neuronal the normal mammalian retina,
12
although dividing cells increase in
progenitor cells (cells able to divide and generate new cells of stressed tissue such as Chx10-null mutants.
13
neuronal lineage) reside within adult retina.
1,2
Pertinently, this debate
raises the possibility of neuronal replacement in man, as observed in RPCs are a majority cell type during development and are easy to
experimental mammals,
3–5
even though single cell cultures confirm isolate and study. Progenitor cells from either developing or adult
that intra-retinal progenitor cells (RPCs) are uncommon.
6
One should tissues will potentially be dividing and differentiating (in various
therefore question whether the presence of retinal neural progenitor stages and pathways of differentiation), and many markers are used
cells or recent progenitor immigrants into the retina explains the to positively or negatively select cell populations of interest (see
functional recovery observed after cell loss without extensive
14–18
Table 1 ). To date, this has been best achieved using cell-surface
destruction of extracellular tissue architecture from macular light flow cytometric phenotypic analysis and isolation via flow cytometric
toxicity
7
or after macula-off retinal detachment.
8–10
cell sorting or, more commonly, magnetic bead cell sorting. Another
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