Recent Advances in Retinal Stem Cell Therapy

Bhattacharya, Sujoy; Gangaraju, Rajashekhar; Chaum, Edward

doi:10.1007/s40610-017-0069-3

Cited by 27 publications

(26 citation statements)

References 119 publications

(112 reference statements)

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“…MSCs are considered a promising cell type with high potential for a regenerative effect in various diseases [ 19 ]. ASCs have gained particular traction as a source of therapeutic MSCs due to their easy isolation from an abundant source.…”

Section: Discussionmentioning

confidence: 99%

“…A number of preclinical animal studies and clinical studies have attempted to develop therapeutic strategies or to halt the progression of TBI with no success to date [ 18 ]. Adult mesenchymal stem cells (MSCs) derived from the stromal vascular fraction of human adipose tissue (ASC, adipose stem/stromal cells) have therapeutic effects in a variety of neurovascular degenerative models [ 19 ]. However, poor cell retention and loss of cell viability and function in the hostile pro-inflammatory environment of injured tissue is a challenge for clinical adoption of cell-based regenerative therapies [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury

Jha

Pentecost

Lenin

et al. 2018

IJMS

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Blast concussions are a common injury sustained in military combat today. Inflammation due to microglial polarization can drive the development of visual defects following blast injuries. In this study, we assessed whether anti-inflammatory factors released by the mesenchymal stem cells derived from adipose tissue (adipose stem cells, ASC) can limit retinal tissue damage and improve visual function in a mouse model of visual deficits following mild traumatic brain injury. We show that intravitreal injection of 1 μL of ASC concentrated conditioned medium from cells pre-stimulated with inflammatory cytokines (ASC-CCM) mitigates loss of visual acuity and contrast sensitivity four weeks post blast injury. Moreover, blast mice showed increased retinal expression of genes associated with microglial activation and inflammation by molecular analyses, retinal glial fibrillary acidic protein (GFAP) immunoreactivity, and increased loss of ganglion cells. Interestingly, blast mice that received ASC-CCM improved in all parameters above. In vitro, ASC-CCM not only suppressed microglial activation but also protected against Tumor necrosis alpha (TNFα) induced endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrate TSG-6 is highly expressed in ASC-CCM from cells pre-stimulated with TNFα and IFNγ but not from unstimulated cells. Our findings suggest that ASC-CCM mitigates visual deficits of the blast injury through their anti-inflammatory properties on activated pro-inflammatory microglia and endothelial cells. A regenerative therapy for immediate delivery at the time of injury may provide a practical and cost-effective solution against the traumatic effects of blast injuries to the retina.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury

Jha

Pentecost

Lenin

et al. 2018

IJMS

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“…This is an important message as clinical trials with stem‐cells (Bhattacharya et al. ; Takashima et al. ) and gene‐vectors (Ku & Pennesi ) have already been initiated in humans.…”

Section: Discussionmentioning

confidence: 99%

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Sørensen

2019

Acta Ophthalmologica

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Background and objectives: Gene-therapy, stem-cell transplantation and surgical robots hold the potential for treatment of currently untreatable retinal degenerative diseases. All of the techniques require entry into the subretinal space, which is a potential space located between the retina and the retinal pigment epithelium (RPE). Knowledge about obstacles and critical steps in relation to subretinal procedures is therefore needed. This thesis explores the functional and histological consequences of separation of the retina from the RPE, extensive RPE damage, a large cut in the retina (retinotomy) and RPE phagocytosis in a porcine model. Methods: Experiments were performed in 106 female domestic pigs of Danish landrace distributed over five studies. Under general anesthesia, different procedures for expansion of the subretinal space were conducted. Outcomes were visual function measured electrophysiologically with multifocal electroretinogram (mfERG) and retinal morphology examined histologically. Study I: The effect of anesthesia on mfERG was examined by repeated recordings for 3 hr in isoflurane or propofol anesthesia. Outcome was mfERG amplitude. Study II: Consequences of a large separation of the photoreceptors from the RPE were examined by injecting a perfluorocarbon-liquid (decalin) into the subretinal space. Two weeks after, in a second surgery, decalin was withdrawn. Outcomes were mfERG and histology 4 weeks after decalin injection. Study III: Extensive RPE damage was examined by expanding the subretinal space with saline and removing large sheets of RPE-cells through a retinotomy. Outcomes were mfERG and histology 2, 4 and 6 weeks after the procedure. Study IV: Consequences of a large retinotomy were examined by similar procedures as in Study III, but in study IV only a few RPE cells were removed. Outcomes were mfERG and histology 2 and 6 weeks after surgery. Study V: Clearance of the subretinal space was examined by injecting fluorescent latex beads of various sizes into the subretinal space. Outcome was histologic location of the beads at different time intervals after the procedure. Results: Study I: MfERG amplitudes decreased linearly as a function of time in propofol or isoflurane anesthesia. Duration of mfERG recording could be decreased without compromising quality, and thereby could time in anesthesia be reduced. Study II: MfERG and histology remained normal after reattachment of a large and 2-week long separation of the photoreceptors and RPE. Repeated entry into the subretinal space was well tolerated. Fluid injection into the subretinal space constitutes a risk of RPE-damage. Study III: Removal of large sheets of retinal pigment epithelial cells triggered a widespread rhegmatogenous-like retinal detachment resulting in visual loss. Study IV: A large retinotomy with limited damage of the RPE was well tolerated, and visual function was preserved. Study V: Subretinal latex beads up to 4 lm were phagocytosed by the RPE and passed into the sub-RPE space. Beads up to 2 lm travelled further through...

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“…Recent advances highlight the feasibility of cell-based therapies for the preservation and regeneration of the retinal neurovascular unit [ 23 ]. We have previously shown that intravitreal injection of adipose-derived stem cells (ASCs) in diabetic rats imparts neurovascular benefits [ 24 ] which were also confirmed by other independent investigators [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse

et al. 2018

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BackgroundEarly-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2Akita mouse model.MethodsIns2Akita mice at 24 weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 μL) or 20× conditioned media from cytokine-primed ASCs (ASC-CM, 1 μL). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3 weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects.ResultsThree weeks post-injection, Ins2Akita mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2Akita mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2Akita mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNFα-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti-inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM.ConclusionsASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2Akita model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1059-y) contains supplementary material, which is available to authorized users.

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Recent Advances in Retinal Stem Cell Therapy

Cited by 27 publications

References 119 publications

Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury

Concentrated Conditioned Media from Adipose Tissue Derived Mesenchymal Stem Cells Mitigates Visual Deficits and Retinal Inflammation Following Mild Traumatic Brain Injury

Subretinal surgery: functional and histological consequences of entry into the subretinal space

Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse

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