Preclinical Evaluation of Long-Term Neuroprotective Effects of BDNF-Engineered Mesenchymal Stromal Cells as Intravitreal Therapy for Chronic Retinal Degeneration in Rd6 Mutant Mice

Abstract

This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.

Pluripotent Stem Cells for the Treatment of Retinal Degeneration: Current Strategies and Future Directions

“…Although beyond the scope of this review, stem cells can also be used to elicit this neurotrophic effect ( Xu and Xu, 2011 ). Recently, intravitreal injection of mesenchymal cells altered to overexpress BDNF has been shown to attenuate apoptosis in RD6 mice ( Lejkowska et al, 2019 ), demonstrating the versatility of stem cell approaches.…”

A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases

“…Several research groups have genetically modified MSCs and tested their efficiency in treatment of retinal diseases in animal models and in vitro studies. Intravitreally injected murine BMSCs engineered to secrete BDNF was found integrated into the outer retinal layers and rescued damaged retinal cells through activation of anti-apoptotic factor B-cell lymphoma-extra-large-protein (BCL-XL) expression in a retinal degenerative rd6 mutant mouse model [ 167 ]. Similarly, neurotrophin-4 (NT-4) engineered murine BMSCs could be detected 3 months post intravitreal transplantation in a preclinical model of acute retinal injury.…”

“…1 Mesenchymal stem cells for treatment of retinal degenerative disorders 1) MSCs have the ability to secrete several neurotrophins which play a cytoprotective role in degenerated retina, found in multiple retinal diseases such as AMD, SD, DR, RP, and Glaucoma [ 63 ]. 2) MSCs can be genetically engineered to express neurotrophins such as NT-4 [ 168 ], BDNF [ 167 ] and anti-angiogenic factor PEDF [ 124 ] that can improve therapy outcome. 3) AMD and DR are associated with pathological angiogenesis which leads to abnormal growth of blood vessels (Choroidal neovascularisation) and haemorrhages within the ocular microenvironment [ 43 , 198 ].…”

<p>Efficient Labeling Of Mesenchymal Stem Cells For High Sensitivity Long-Term MRI Monitoring In Live Mice Brains</p>

“…For the neurodegenerative diseases, brain injuries, and stroke, the use of therapeutic mesenchymal stem cells (MSCs) showed promising therapeutic effects due to their capability to induce regeneration and neurogenesis, and modulate the vascularization and inflammation of the affected tissues. 1 The therapeutic effects of MSCs are attributed to their capability of producing various neurotrophic factors such as brain-derived neurotrophic factor (BDNF), 2,3 glial-cell-derived neurotrophic factor (GDNF), 4 stromal cell-derived factor 1 (SDF1), 5 and angiogenic molecules. 6 One important endogenous protein that is recently attracting the attention of neuroscientists due to its possible roles in neuroprotection is the fibroblast growth factor-21 (FGF21).…”