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Neuroprotective effects of bone marrow Sca-1⁺ cells against age-related retinal degeneration in OPTN E50K mice.

ABSTRACT: Glaucoma is characterized by retinal ganglion cell (RGC) death, the underlying mechanisms of which are still largely unknown. An E50K mutation in the Optineurin (OPTN) gene is a leading cause of normal-tension glaucoma (NTG), which directly affects RGCs in the absence of high intraocular pressure and causes severe glaucomatous symptoms in patients. Bone marrow (BM) stem cells have been demonstrated to play a key role in regenerating damaged tissue during ageing and disease through their trophic effects and homing capability. Here, we separated BM stem cells into Sca-1⁺ and Sca-1^- cells and transplanted them into lethally irradiated aged OPTN E50K mice to generate Sca-1⁺ and Sca-1^- chimaeras, respectively. After 3 months of BM repopulation, we investigated whether Sca-1⁺ cells maximized the regenerative effects in the retinas of NTG model mice with the OPTN E50K mutation. We found that the OPTN E50K mutation aggravated age-related deficiency of neurotrophic factors in both retinas and BM during NTG development, leading to retinal degeneration and BM dysfunction. Sca-1⁺ cells from young healthy mice had greater paracrine trophic effects than Sca-1^- cells and Sca-1⁺ cells from young OPTN E50K mice. In addition, Sca-1⁺ chimaeras demonstrated better visual functions than Sca-1^- chimaeras and untreated OPTN E50K mice. More Sca-1⁺ cells than Sca-1^- cells were recruited to repair damaged retinas and reverse visual impairment in NTG resulting from high expression levels of neurotrophic factors. These findings indicated that the Sca-1⁺ cells from young, healthy mice may have exhibited an enhanced ability to repair retinal degeneration in NTG because of their excellent neurotrophic capability.

SUBMITTER: Liu X

PROVIDER: S-EPMC8203676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeTo evaluate the therapeutic potential and safety of intravitreal injections of bone marrow mononuclear fraction (BMMF) containing CD34+ cells in patients with atrophic age-related macular degeneration (AMD).MethodsTen patients with atrophic AMD and best-corrected visual acuity (BCVA) in the worse-seeing eye of ≤20/100 were enrolled in this study. The bone marrow from all patients was aspirated and processed for mononuclear cell separation. A 0.1 mL suspension of BMMF CD34+ cells was injected into the vitreous cavity of the worse-seeing eye. Patients were evaluated at Baseline and 1,3,6,9 and 12 months after injection. Ophthalmic evaluation included BCVA measurement, microperimetry, infrared imaging, fundus autofluorescence and SD-optical coherence tomography at all study visits. Fluorescein angiography was performed at Baseline and at 6 and 12 months after intravitreal therapy.ResultsAll patients completed the 6-month follow-up, and six completed the 12-month follow-up. Prior to the injection, mean BCVA was 1.18 logMAR (20/320-1), ranging from 20/125 to 20/640-2, and improved significantly at every follow-up visit, including the 12-month one, when BCVA was 1.0 logMAR (20/200) (P<0.05). Mean sensitivity threshold also improved significantly at 6, 9 and 12 months after treatment (P<0.05). Considering the area of atrophy identified by fundus autofluorescence, significant mean BCVA and mean sensitivity threshold improvement were observed in patients with the smallest areas of atrophy. Fluorescein angiography did not identify choroidal new vessels or tumor growth.ConclusionThe use of intravitreal BMMF injections in patients with AMD is safe and is associated with significant improvement in BCVA and macular sensitivity threshold. Patients with small areas of atrophy have a better response. The paracrine effect of CD34+ cells may explain the functional improvement observed; however, larger series of patients are necessary to confirm these preliminary findings.

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Neuroprotective effects of bone marrow Sca-1+ cells against age-related retinal degeneration in OPTN E50K mice.

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Neuroprotective effects of bone marrow Sca-1⁺ cells against age-related retinal degeneration in OPTN E50K mice.