Editors Selection IGR 21-4

Basic Science: Stem Cells and RGC Replacement

Keith Martin

Comment by Keith Martin on:

91650 Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells, Zhang KY; Tuffy C; Mertz JL et al., Stem cell reports, 2021; 16: 149-167

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The ability to restore vision in degenerative optic nerve diseases such as glaucoma by transplantation of retinal ganglion cells (RGC) would be transformative, but many challenges remain. A key challenge is to achieve effective integration of transplanted cells into the host retina, with the inner limiting membrane the first barrier that must be overcome.

In an elegant series of experiments published in Stem Cell Reports, Zhang et al. cultured human embryonic stem cell (hES) derived RGC on mouse retinal explants and explored their survival and integration. The researchers showed that the inner limiting membrane is a significant barrier to integration of cultured cells.

The inner limiting membrane is a significant barrier to integration of cultured cells

Extracellular matrix digestion using a variety of proteolytic enzymes achieved ILM disruption, but some of the protocols caused more widespread retinal damage. However, the authors nicely demonstrated that using a low dose of pronase E preserved glial reactivity and retinal architecture whilst facilitating neurite outgrowth into the host retina.

They were also careful to provide evidence that fluorescently labelled cells extending neurites in the host retina were actually transplanted cells, and not host cells that had taken up labels released by transplanted cells ‐ a major issue in some previous studies. They did this by transplanting red labelled RGC onto retinas from animals where all cells express green fluorescent protein. Thus, a cell which fluoresces red but not green is proven to be a transplanted cell.

The authors appropriately discuss the pros and cons of using explant models compared to in-vivo experiments, and they caution that surgical peeling of the ILM may be an alternative solution in human eyes prior to cell transplantation. However, they should be congratulated on a study which demonstrates a thoughtful and practical approach to a problem of considerable translational relevance, advancing our understanding in the process.

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