Restoration of vision after transplantation of photoreceptors

Pearson, R. A.; Barber, Amanda C.; Rizzi, Matteo; Hippert, Claire; Xue, Tian; West, Emma L.; Durán, Yanaí; Smith, Alexander J.; Chuang, Jen-Zen; Azam, Selina A.; Luhmann, Ulrich F O; Benucci, Andrea; Sung, Ching Hwa; Bainbridge, James; Carandini, Matteo; Yau, King–Wai; Sowden, Jane C.; Ali, Robin R.

doi:10.1038/nature10997

Cited by 443 publications

(484 citation statements)

References 21 publications

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“…Cells isolated at the correct ontogenetic stage from the developing retina were able to integrate into the host retina, form functional synaptic connections, and mediate light-stimulated behavior in mice with retinal degeneration [1,2]. However, the equivalent stage of development from which postmitotic photoreceptor precursors could be derived in humans are second trimester fetuses, an ethically and logistically challenging source.…”

Section: Introductionmentioning

confidence: 99%

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

119

116

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Retinal degeneration is a leading cause of irreversible blindness in the developed world. Differentiation of retinal cells, including photoreceptors, from both mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), potentially provide a renewable source of cells for retinal transplantation. Previously, we have shown both the functional integration of transplanted rod photoreceptor precursors, isolated from the postnatal retina, in the adult murine retina, and photoreceptor cell generation by stepwise treatment of ESCs with defined factors. In this study, we assessed the extent to which this protocol recapitulates retinal development and also evaluated differentiation and integration of ESC-derived retinal cells following transplantation using our established procedures. Optimized retinal differentiation via isolation of Rax.GFP retinal progenitors recreated a retinal niche and increased the yield of Crx 1 and Rhodopsin 1 photoreceptors. Rod birth peaked at day 20 of culture and expression of the early photoreceptor markers Crx and Nrl increased until day 28. Nrl levels were low in ESC-derived populations compared with developing retinae. Transplantation of early stage retinal cultures produced large tumors, which were avoided by prolonged retinal differentiation (up to day 28) prior to transplantation. Integrated mature photoreceptors were not observed in the adult retina, even when more than 60% of transplanted ESCderived cells expressed Crx. We conclude that exclusion of proliferative cells from ESC-derived cultures is essential for effective transplantation. Despite showing expression profiles characteristic of immature photoreceptors, the ESC-derived precursors generated using this protocol did not display transplantation competence equivalent to precursors from the postnatal retina. STEM CELLS

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Section: Introductionmentioning

confidence: 99%

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

119

116

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“…Here we show, for the first time, that graft architecture can be highly variable at the time of transplantation, which could represent a considerable source of treatment variation among recipients and across the fundus. In this regard, bimodal imaging allows for early detection of a central problem inherent to cellsuspension therapeutics: undesired graft aggregation resulting in ischemia (reviewed by Robey et al 26 ) and/or spatial inhibition of functional connections, such as the highly limited contact observed between bolus PPC-grafts and host RPE 9 -a common architecture seen here and in other studies 7,9,27 ). Conversely, bimodal imaging can also detect extensive graft dispersion, which can leave insufficient density of cells for functional benefit, as small quantities of integrating PPCs are unlikely to rescue vision.…”

Section: Real-time Detection Of Graft Placement and Survivalmentioning

confidence: 62%

“…Although various functional assessments can be used to evaluate photoreceptor graft success, [5][6][7] these can only be used in long-term studies once functional integration has been achieved. Remarkably, a handful of studies have shown some restoration of vision in photoreceptor precursor cell (PPC) recipients, [6][7][8][9] though graft integration and survival remains too low to be clinically relevant.…”

Section: Introductionmentioning

confidence: 99%

“…Remarkably, a handful of studies have shown some restoration of vision in photoreceptor precursor cell (PPC) recipients, [6][7][8][9] though graft integration and survival remains too low to be clinically relevant. Short-term assessment in serial studies aimed at addressing these barriers currently relies on imaging, such as ophthalmoscopy and end point histology.…”

Section: Introductionmentioning

confidence: 99%

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Bimodal in vivo imaging provides early assessment of stem-cell-based photoreceptor engraftment

Laver

Metcalfe

Szczygiel

et al. 2015

Eye

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Purpose Subretinal transplantation of stem-cell-derived photoreceptor precursor cells (PPCs) is a promising and innovative approach to treating a range of blinding diseases. However, common barriers to efficient preclinical transplantation comes in the form of suboptimal graft architecture, limited graft survival, and immune-rejection, each of which cannot be assessed using conventional in vivo imaging (ie, rodent ophthalmoscopy). With the majority of PPCs reported to die within the first few weeks after transplantation, understanding the mechanisms of graft failure, and ultimately devising preventative methods, currently relies on lengthy end point histology.To address these limitations, we hypothesized that combining two imaging modalities, optical coherence tomography (OCT) and fluorescence confocal scanning laser ophthalmoscopy (fcSLO), could provide a more rapid and comprehensive view of PPC engraftment. Methods Human ESC-derived PPCs were transplanted into 15 retinal dystrophic rats that underwent bimodal imaging at 0, 8, and 15 days posttransplant. Results Bimodal imaging provided serial detection of graft: placement, architecture, and survival; each undetectable under ophthalmoscopy. Bimodal imaging determined graft placement to be either: subretinal (n = 7), choroidal (n = 4), or vitreal (n = 4) indicating neural retinal perforation. Graft architecture was highly variable at the time of transplantation, with notable redistribution over time, while complete, or near complete, graft loss was observed in the majority of recipients after day 8. Of particular importance was detection of vitreal aggregates overlying the graft-possibly an indicator of host-site inflammation and rejection. Conclusion Early real-time feedback of engraftment has the potential to greatly increase efficiency of preclinical trials in cell-based retinal therapeutics.

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“…Ali and his colleagues, for example, have shown that when precursors to rod cellsphotoreceptors that are active in dim lightare transplanted into mouse eyes, they connect with other cells in the retina and can restore vision 8 . They also showed that the rods can be grown from mouse embryonic stem cells and can mature and integrate into the retina 9 .…”

Section: R E G E N E R a T I O N G A M Ementioning

confidence: 99%

Curing blindness: Vision quest

Lok¹

2014

Nature

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Restoration of vision after transplantation of photoreceptors

Cited by 443 publications

References 21 publications

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors

Bimodal in vivo imaging provides early assessment of stem-cell-based photoreceptor engraftment

Curing blindness: Vision quest

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