/pdf/turning-lead-into-gold-reprogramming-retinal-cells-to-cure-5ag7oomoff.pdf

Turning lead into gold: reprogramming retinal cells to cure blindness.

Inherited and age-associated vision loss is often associated with degeneration of the cells of the retina, the light-sensitive layer at the back of the eye. The mammalian retina, being a postmitotic neural tissue, does not have the capacity to repair itself through endogenous regeneration. There has been considerable excitement for the development of cell replacement approaches since the isolation and development of culture methods for human pluripotent stem cells, as well as the generation of induced pluripotent stem cells. This has now been combined with novel three-dimensional organoid culture systems that closely mimic human retinal development in vitro. In this review, we cover the current state of the field, with emphasis on the cell delivery challenges, role of the recipient immunological microenvironment, and challenges related to connectivity between transplanted cells and host circuitry both locally and centrally to the different areas of the brain.

Factors Affecting Stem Cell-Based Regenerative Approaches in Retinal Degeneration.

Background and Objectives To examine whether ischemic retinal ganglion cells (RGCs) will be salvaged from cell death by human adipose-derived mesenchymal stem cells (ADSCs) in an organotypic retina model. Methods and Results Deprived of arterial oxygen supply, whole mice retinas were cultured as an ex vivo organotypic cultures on an insert membrane in a 24-well plate. The therapeutic potential of ADSCs was examined by co-culture with organotypic retinas. ADSCs were seeded on top of the RGCs allowing direct contact, or at the bottom of the well, sharing the same culture media and allowing a paracrine activity. The number of surviving RGCs was assessed using Brn3a staining and confocal microscopy. Cytokine secretion of ADSCs to medium was analyzed by cytokine array. When co-cultured with ADSCs, the number of surviving RGCs was similarly significantly higher in both treatment groups compared to controls. Analysis of ADSCs cytokines secretion profile, showed secretion of anti-apoptotic and pro-proliferative cytokines (threshold>1.4). Transplantation of ADSCs in a co-culture system with organotypic ischemic retinas resulted in RGCs recovery. Since there was no advantage to direct contact of ADSCs with RGCs, the beneficial effect seen may be related to paracrine activity of ADSCs. Conclusions These data correlated with secretion profile of ADSCs’ anti-apoptotic and pro-proliferative cytokines.

https://www.ijstemcell.com/journal/download_pdf.php?doi=10.15283/ijsc22041

Regenerative Effect of Adipose Derived Mesenchymal Stem Cells on Ganglion Cells in the Hypoxic Organotypic Retina Culture

Vision is one of the major pathways for receiving external information in vertebrates. The optic nerve connects the retina to the brain and relays visual coding signals to the corresponding cortical regions. It is widely believed that the retinal ganglion cells (RGCs) and optic nerve cannot regenerate in mammals, and their injuries are the most common causes of blindness. Several extrinsic and intrinsic factors limit axonal regeneration in the optic nerve. Elimination of extrinsic inhibitory factors and activation of intrinsic pro-regenerative factors enable a small number of damaged axons to regenerate and improve visual functions in a limited manner. Furthermore, transplantation of stem cell-derived RGCs or <italic>in vivo</italic> reprogramming of Müller and amacrine cells into RGCs can restore part of the vision, which provides insights into the future therapy for various neurodegenerative disorders, such as glaucoma. This review summarizes the recent studies on axon and retinal cell regeneration after optic nerve injury in vertebrates.

Optic nerve repair and regeneration in vertebrates

Stem cell-based organoid cultures as innovative approaches for ocular repair and regeneration

SUMMARY Degeneration of retinal ganglion cells (RGCs) and their axons underlies vision loss in glaucoma and various optic neuropathies. There are currently no treatments available to restore lost vision in patients affected by these diseases. Regenerating RGCs and reconnecting the retina to the brain represent an ideal therapeutic strategy; however, mammals do not have a reservoir of retinal stem/progenitor cells poised to produce new neurons in adulthood. Here, we regenerated RGCs in adult mice by direct lineage reprogramming of retinal interneurons. We successfully converted amacrine and displaced amacrine interneurons into RGCs, and observed that regenerated RGCs projected axons into brain retinorecipient areas. They convey visual information to the brain in response to visual stimulation, and are able to transmit electrical signals to postsynaptic neurons, in both normal animals and in a diseased model. The generation of functional RGCs in adult mammals points to a therapeutic strategy for vision restoration in patients.

https://biorxiv.org/content/10.1101/2020.07.16.203497v1.full.pdf

Regeneration of Functional Retinal Ganglion Cells by Neuronal Identity Reprogramming

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Regeneration of Functional Retinal Ganglion Cells by Neuronal Identity Reprogramming