Loss of photoreceptor potential from retinal progenitor cell cultures, despite improvements in survival

Mansergh, Fiona C.; Vawda, Reaz; Millington‐Ward, Sophia; Kenna, Paul F.; Haas, Jochen; Gallagher, Clair; Wilson, John H.; Humphries, Peter; Ader, Marius; Farrar, G. Jane

doi:10.1016/j.exer.2010.07.003

Cited by 21 publications

(27 citation statements)

References 45 publications

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“…Current treatment approaches, such as nutritional supplements [6], growth factors [7–9], transplantation of RPE [10, 11], or retinal progenitors [12] target early disease stages with the aim to delay retinal degeneration and do not aim to replace lost photoreceptors. Replacing photoreceptors with transplants of dissociated photoreceptor precursors has been demonstrated, but the cells can only develop full photoreceptor morphology when a photoreceptor layer is still present [13–15] and do not survive long term because they can elicit immune responses [16]. In contrast, transplantation of fetal-derived retinal sheets (with and without its RPE) has shown long-term photoreceptor replacement and visual restoration in animal models [17–19] and visual improvements in phase 2 clinical trials [20].…”

Section: Introductionmentioning

confidence: 99%

A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression

Seiler

Aramant

Jones

et al. 2014

Graefes Arch Clin Exp Ophthalmol

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Purpose The goal of this study was to develop an immunodeficient rat model of retinal degeneration (RD nude rats) that will not reject transplanted human cells. Methods SD-Tg(S334ter)3Lav females homozygous for a mutated mouse rhodopsin transgene were mated with NTac:NIH-Whn (NIH nude) males homozygous for the Foxn1rnu allele. Through selective breeding, a new stock, SD-Foxn1 Tg(S334ter)3Lav (RD nude) was generated such that all animals were homozygous for the Foxn1rnu allele and either homo- or hemizygous for the S334ter transgene. PCR-based assays for both the Foxn1rnu mutation and the S334ter transgene were developed for accurate genotyping. Immunodeficiency was tested by transplanting sheets of hESC-derived neural progenitor cells to the subretinal space of RD nude rats, and, as a control, NIH nude rats. Rats were killed between 8 and 184 days after surgery, and eye sections were analyzed for human, neuronal, and glial markers. Results After transplantation to RD nude and to NIH nude rats, hESC-derived neural progenitor cells differentiated to neuronal and glial cells, and migrated extensively from the transplant sheets throughout the host retina. Migration was more extensive in RD nude than in NIH nude rats. Already 8 days after transplantation, donor neuronal processes were found in the host inner plexiform layer. In addition, host glial cells extended processes into the transplants. The host retina showed the same photoreceptor degeneration pattern as in the immunocompetent SD-Tg(S334ter)3Lav rats. Recipients survived well after surgery. Conclusions This new rat model is useful for testing the effect of human cell transplantation on the restoration of vision without interference of immunosuppression.

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Section: Introductionmentioning

confidence: 99%

A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression

Seiler

Aramant

Jones

et al. 2014

Graefes Arch Clin Exp Ophthalmol

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“…41 Morphological analysis showed remarkable survival of donor GFP-positive cells 4 weeks after transplantation with the majority of the donor cells remaining recoverin-positive, losing Ki-67 expression, and a few acquiring rhodopsin expression.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants

Abud

Baranov

Hicks

et al. 2015

Trans. Vis. Sci. Tech.

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Purpose: The development of photoreceptor replacement therapy for retinal degenerative disorders requires the identification of the optimal cell source and immunosuppressive regimen in a large animal model. Allotransplants are not acutely rejected in swine subretinal space, although it is not known if survival can be improved with immunosuppression. Here we investigated the survival and integration of expanded pig retinal progenitor cells (pRPCs) in normal recipients with and without transient anti-inflammatory suppression.Methods: pRPCs were derived from the neural retina of E60 GFP transgenic pigs, expanded for six passages, characterized, and transplanted into the subretinal space of 12 pigs. Six recipients received a single intravitreal injection of rapamycin and dexamethasone.Results: pRPCs expressed the photoreceptor development genes Sox2, Pax6, Lhx2, Crx, Nrl, and Recoverin in vitro. Transplanted cells were identified in 9 out of 12 recipients 4 weeks after the injection. pRPCs integrated primarily into the photoreceptor inner segment layer and outer nuclear layer with single cells present in the inner nuclear layer. Donor cells remained recoverin-positive and acquired rhodopsin. We did not observe any signs of graft proliferation. The immunosuppression did not affect the survival or distribution of grafts. No macrophage infiltration or loss of retinal structure was observed in either group.Conclusions: Local immunosuppression with rapamycin and dexamethasone does not improve the outcome of pRPC allotransplantation into the subretinal space.Translational Relevance: Survival and integration of pRPC together with the lack of graft proliferation suggests that allogeneic RPC transplantation without transient immunosuppression is a favorable approach for photoreceptor cell replacement.

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“…14 Cells were differentiated via withdrawal of epidermal growth factor for 5 days, then harvested for injection. Cultured eGFP RPCs were harvested for injection as described previously, 14 resuspended in HBSS such that 3 ml contained 200 000 cells, and placed on ice until injection. MEFs were isolated and cultured as described previously.…”

Section: Cell Culturementioning

confidence: 99%

“…[12][13][14]18,19 We investigated whether newly-specified RGCs could be used intravitreally to treat optic neuropathies, using a rotenone-induced model of LHON. Retinas were dissociated from embryonic day 16 and 17 (E16 and E17) and postnatal Day2 (pn2) eGFP mice; within the timeframe for RGC specification.…”

Section: Stem Cell Transplantationmentioning

confidence: 99%

“…Cultured RPCs lose the ability to form photoreceptors and, when differentiated, form a mixture of glial cells with some neurons. 14,21 These cells are now thought to generate a neural/glial stem cell line with oligodendroglial potential, similar to neural stem cells isolated from the brain. 21 We injected 200 000 postnatallyderived early passage RPCs into 1.5 mM rotenone-treated retinas, transplanting both proliferating RPCs, and those that had undergone initial differentiation by withdrawal of Fgf2 from the medium for 5 days.…”

Section: Stem Cell Transplantationmentioning

confidence: 99%

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Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy

et al. 2014

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Primary mitochondrial disorders occur at a prevalence of one in 10 000; B50% of these demonstrate ocular pathology. Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder. LHON results from retinal ganglion cell pathology, which leads to optic nerve degeneration and blindness. Over 95% of cases result from one of the three common mutations in mitochondrial genes MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain. Various therapies for LHON are in development, for example, intravitreal injection of adeno-associated virus carrying either the yeast NDI1 gene or a specific subunit of mammalian Complex I have shown visual improvement in animal models. Given the course of LHON, it is likely that in many cases prompt administration may be necessary before widespread cell death. An alternative approach for therapy may be the use of stem cells to protect visual function; this has been evaluated by us in a rotenone-induced model of LHON. Freshly dissected embryonic retinal cells do not integrate into the ganglion cell layer (GCL), unlike similarly obtained photoreceptor precursors. However, cultured retinal progenitor cells can integrate in close proximity to the GCL, and act to preserve retinal function as assessed by manganese-enhanced magnetic resonance imaging, optokinetic responses and ganglion cell counts. Cell therapies for LHON therefore represent a promising therapeutic approach, and may be of particular utility in treating more advanced disease. INTRODUCTIONPrimary mitochondrial disorders (those caused by mutations in the mitochondrial genome) occur at a prevalence of B1 in 10 000, with 1 in 200 individuals carrying at-risk mutations. 1 Approximately 50% demonstrate some form of ocular pathology. 2 Mitochondria provide energy in the form of ATP generated by oxidative phosphorylation; therefore, mitochondrial mutations primarily affect tissues with the greatest energy requirements, such as the retina, the inner ear, central and peripheral nervous systems and cardiac and skeletal muscle. 2,3 Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial disorder, with a prevalence of B1 in 31 000-50 000 in northern Europe. The prevalence of at-risk carriers is much higher, estimated at 1 in 8 500 in the UK; furthermore, primary LHON mutations were found in 1 out of 350 neonatal umbilical cord samples. 1,4 LHON is maternally inherited, often results from homoplasmy of the causative mitochondrial mutation, and is incompletely penetrant; visual loss occurs in 50% of males and 10% of females. Symptoms result from retinal ganglion cell (RGC) pathology, which leads to RGC death via apoptosis, resulting in optic nerve degeneration and subsequent blindness. Nonocular symptoms of mitochondrial dysfunction may also be present. 1,4 Although many mutations implicated in LHON have been described, 90-95% of the cases result from one of the three common mutations in mitochondrial genes including MTND1, MTND4 and MTND6, which encode elements of ...

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Loss of photoreceptor potential from retinal progenitor cell cultures, despite improvements in survival

Cited by 21 publications

References 45 publications

A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression

A new immunodeficient pigmented retinal degenerate rat strain to study transplantation of human cells without immunosuppression

The Effect of Transient Local Anti-inflammatory Treatment on the Survival of Pig Retinal Progenitor Cell Allotransplants

Cell therapy using retinal progenitor cells shows therapeutic effect in a chemically-induced rotenone mouse model of Leber hereditary optic neuropathy

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