Biomedicines · 9 authors, 2 centres
This summary was generated by AI from a single paper. It has not been reviewed by a clinician and is not clinical advice. Verify against the source before acting on it.
Subconjunctival injection of sirolimus-pretreated mesenchymal stem cells (MSCs) significantly improved retinal function and reduced retinal thinning in a rat model of diabetic retinopathy (DR). The treatment restored electroretinogram amplitudes and preserved inner nuclear and photoreceptor layer thickness compared to untreated DR rats. This approach offers a potential new therapy for DR by enhancing MSC survival and efficacy in hyperglycemic conditions.
**Background:** Diabetic retinopathy (DR) is a leading cause of vision loss in adults, driven by hyperglycemia-induced microvascular damage, oxidative stress, and inflammation. Current treatments (laser photocoagulation, anti-VEGF injections) have limitations, including tissue destruction and short-lived effects. Mesenchymal stem cells (MSCs) offer regenerative and paracrine benefits but suffer from poor survival in hyperglycemic environments. Sirolimus (rapamycin) pretreatment enhances MSC survival, autophagy, and stress resistance. This study investigated whether subconjunctival injection of sirolimus-pretreated MSCs improves retinal function and structure in a rat model of DR.
**Methods:** Twenty-five male Sprague-Dawley rats were divided into four groups: intact control (INT, n=8), DR (n=7), DR with MSC injection (DR-MSC, n=4), and DR with sirolimus-pretreated MSC injection (DR-MSC-S, n=6). Diabetes was induced by intraperitoneal streptozotocin (55 mg/kg). After 10 weeks, DR was confirmed by electroretinography (ERG). Subconjunctival injections (1×10^5 cells in 10 µL PBS) were performed at 11 and 12 weeks post-diabetes induction. Sirolimus pretreatment (100 nM for 24 h) was applied to MSCs for the DR-MSC-S group. ERG was repeated at 14 weeks, and histological evaluation (H&E staining) was performed at 18 weeks post-diabetes induction. Body weight and blood glucose were monitored throughout.
**Key Results:** At 10 weeks, diabetic rats showed significantly lower ERG amplitudes than INT (flash b-wave: 73.84±21.25 µV vs. 153.2±56.59 µV; flicker: 66.41±24.28 µV vs. 118.59±32.29 µV; p<0.01). At 14 weeks, the DR-MSC-S group had significantly higher flicker amplitude (107.30±23.01 µV) than DR (48.28±17.03 µV) and DR-MSC (88.27±23.91 µV; p<0.01), and was not statistically different from INT (147.00±28.62 µV). Flash b-wave amplitude in DR-MSC-S (148.50±17.32 µV) was significantly higher than DR (60.21±22.31 µV) and DR-MSC (89.53±18.46 µV; p<0.01). Histologically, total retinal thickness was greater in DR-MSC-S (215.90±12.04 µm) than DR (179.60±16.18 µm) and DR-MSC (191.80±18.78 µm; p<0.01). Inner nuclear layer thickness in DR-MSC-S (38.45±6.84 µm) was significantly greater than DR (31.21±5.30 µm; p<0.01) and similar to INT (38.70±5.93 µm). Photoreceptor layer thickness in DR-MSC-S (32.17±4.93 µm) was significantly greater than DR (25.43±3.56 µm; p<0.01) and comparable to INT (33.13±4.19 µm). No significant differences in body weight or blood glucose were observed among diabetic groups, indicating no systemic effect.
**Clinical Implications:** This study demonstrates that sirolimus-pretreated MSCs, delivered via subconjunctival injection, can improve retinal function and mitigate structural damage in a rat DR model. The subconjunctival route offers a less invasive alternative to intravitreal injections, with lower risk of complications. Sirolimus pretreatment likely enhances MSC survival and paracrine activity under hyperglycemic stress, addressing a key limitation of MSC therapy. These findings support further investigation into sirolimus-pretreated MSCs as a potential treatment for DR, though long-term efficacy and optimal dosing require additional study.