Human primitive mesenchymal stem cell-derived retinal progenitor cells improved neuroprotection, neurogenesis, and vision in rd12 mouse model of retinitis pigmentosa

Abstract

Background Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP. Methods Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina. Results Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways. Conclusions Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice.

Retinitis Pigmentosa: Novel Therapeutic Targets and Drug Development

“…Brown and colleagues used primitive MSC-derived retinal progenitor cells in rd12 mouse models. They tracked PKH26 dyed cells and found that cells were able to integrate and counter inflammation [ 154 ]. Overall, the advantages of BMSCs include their ability to migrate towards lesion sites, the ability for trans-differentiation, and the simplicity in extracting and manipulating CD34+ cells.…”

Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies

“…RPCs can be derived from ESCs, iPSCs and MSCs, among others. These cells show promising results with increased BCVA outcomes in injected eyes but are relatively self-limiting regarding expansion compared to pluripotent cell lines [ 319 , 320 ]. RPCs also retain their capacity to differentiate in preclinical studies, which poses challenges post-transplantation [ 311 , 319 , 321 ].…”

“…These cells show promising results with increased BCVA outcomes in injected eyes but are relatively self-limiting regarding expansion compared to pluripotent cell lines [ 319 , 320 ]. RPCs also retain their capacity to differentiate in preclinical studies, which poses challenges post-transplantation [ 311 , 319 , 321 ]. MSCs, with their lower cell potency, are considered safer and have more long-term data on the risk of tumorigenesis.…”

Neuroinflammation in retinitis pigmentosa: Therapies targeting the innate immune system

“…Activation of JAK/STAT signaling has a protective effect on the RP retina. pMSC-derived retinal progenitor cell transplantation increased PR preservation in rd12 mice, and this protection was partially mediated by activation of the JAK/STAT pathway ( 100 ).…”