Neurally Selected Embryonic Stem Cells Induce Tumor Formation after Long-Term Survival following Engraftment into the Subretinal Space

Arnhold, Stefan; Klein, Helmut W.; Semkova, Irina; Addicks, Klaus; Schraermeyer, Ulrich

doi:10.1167/iovs.03-1108

Cited by 194 publications

(139 citation statements)

References 22 publications

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“…126,127 MSCs are a type of adult stem cells 11 that have been intensively explored by Eliopoulos et al 128 for delivery of EPO to correct anemia successfully in mice. 129 We have previously transplanted MSCs derived from human Wharton's Jelly into the subretinal layer of the Royal College of Surgeon's rats and found that these cells had the ability to differentiate into retinal cells, which was in concurrance with other study. 130,131 The use of MSCs as a vector to deliver EPO 132 through intravenous injection for ocular disorders is feasible in the future as these cells could home into the inflammatory site 133,134 and cross the BRB.…”

Section: Future Directionssupporting

confidence: 84%

Revisiting the role of erythropoietin for treatment of ocular disorders

Ding

Leow

Munisvaradass

et al. 2016

Eye

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Erythropoietin (EPO) is a glycoprotein hormone conventionally thought to be responsible only in producing red blood cells in our body. However, with the discovery of the presence of EPO and EPO receptors in the retinal layers, the EPO seems to have physiological roles in the eye. In this review, we revisit the role of EPO in the eye. We look into the biological role of EPO in the development of the eye and the physiologic roles that it has. Apart from that, we seek to understand the mechanisms and pathways of EPO that contributes to the therapeutic and pathological conditions of the various ocular disorders such as diabetic retinopathy, retinopathy of prematurity, glaucoma, age-related macular degeneration, optic neuritis, and retinal detachment. With these understandings, we discuss the clinical applications of EPO for treatment of ocular disorders, modes of administration, EPO formulations, current clinical trials, and its future directions.

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Section: Future Directionssupporting

confidence: 84%

Revisiting the role of erythropoietin for treatment of ocular disorders

Ding

Leow

Munisvaradass

et al. 2016

Eye

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“…The presence of tumors following ESC and ESC-derived transplantation to the eye has been shown previously in several other studies [36][37][38][39]. In transplantations to the brain, selection of Sox1.GFP þ cells and culture prior to transplantation attenuated tumor formation [40].…”

Section: Discussionmentioning

confidence: 53%

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

West¹,

Gonzalez‐Cordero²,

Hippert³

et al. 2012

Stem Cells

118

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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“…Importantly, functional rescue of the outer retina in an animal model is observed after transplantation of ESC-NSCs [48][49][50]. Teratomas were not observed after transplantation of ESC-NSCs, although tumors were observed with related neurally selected ESCs [51]. Directing ESCs toward NSCs that express retinal markers prior to transplantation improves integration and increases the number of photoreceptor cell progeny, whereas tumor formation using this protocol was not observed for as much as 6 weeks [32].…”

Section: Neural Stem Cellsmentioning

confidence: 91%

“…Teratomas form even after transplantation of ESCs that have undergone neural selection [51]. Although pre-transplantation differentiation of ESC into RSCs, NSCs, or RPE decreases tumor formation, tumorigenicity remains a challenge for the safe clinical use of ESCs [64].…”

Section: Pluripotent Stem Cellsmentioning

confidence: 99%

Stem Cells for Retinal Replacement Therapy

Stern

Temple

2011

Neurotherapeutics

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Retinal degenerative disease has limited therapeutic options and the possibility of stem cell-mediated regenerative treatments is being actively explored for these blinding retinal conditions. The relative accessibility of this central nervous system tissue and the ability to visually monitor changes after transplantation make the retina and adjacent retinal pigment epithelium prime targets for pioneering stem cell therapeutics. Prior work conducted for several decades indicated the promise of cell transplantation for retinal disease, and new strategies that combine these established surgical approaches with stem cell-derived donor cells is ongoing. A variety of tissue-specific and pluripotent-derived donor cells are being advanced to replace lost or damaged retinal cells and/or to slow the disease processes by providing neuroprotective factors, with the ultimate aim of long-term improvement in visual function. Clinical trials are in the early stages, and data on safety and efficacy are widely anticipated. Positive outcomes from these stem cell-based clinical studies would radically change the way that blinding disorders are approached in the clinic.

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Neurally Selected Embryonic Stem Cells Induce Tumor Formation after Long-Term Survival following Engraftment into the Subretinal Space

Cited by 194 publications

References 22 publications

Revisiting the role of erythropoietin for treatment of ocular disorders

Revisiting the role of erythropoietin for treatment of ocular disorders

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

Stem Cells for Retinal Replacement Therapy

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