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WGC-2021

Editors Selection IGR 22-1

Basic Science: Stem cell replacement of retinal ganglion cells - I

Thomas Johnson

Comment by Thomas Johnson on:

92498 The role of PGS/PCL scaffolds in promoting differentiation of human embryonic stem cells into retinal ganglion cells, Behtaj S; Karamali F; Najafian S et al., Acta biomaterialia, 2021; 126: 238-248


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Regenerative medicine approaches to retinal ganglion cell (RGC) replacement hold considerable potential for enabling vision restorative treatments for glaucoma.1 One major milestone for RGC replacement is efficient generation of bona fide human RGCs that can integrate into the mature visual neurocircuitry. Recently, several laboratories have developed methodologies to differentiate RGCs from pluripotent cells in adherent cell culture and from retinal organoids.2-8 However, the relative strengths and weaknesses of various differentiation protocols remains unclear. Photoreceptor transplantation experiments suggests that retinal engraftment may be enhanced by transplanting donor cells on a biocompatible scaffold,9 although the application of biomaterial support to RGC transplantation has been more limited.10 Following on prior work comparing biomaterial scaffold compositions' ability to support retinal progenitor cell (RPC) attachment and proliferation,11 Behtaj et al. describe an approach for RGC differentiation within an aligned, electrospun biomaterial scaffold consisting of polg(glycersol sebactate) (PGS) and poly(ε-caprolactone) (PCL).12

Photoreceptor transplantation experiments suggests that retinal engraftment may be enhanced by transplanting donor cells on a biocompatible scaffold, although the application of biomaterial support to RGC transplantation has been more limited

The authors characterize the scaffolds to show that the PGS/PCL generate relatively homogenous nanofibers of 2.3 ± 0.3 µm diameter that are highly aligned and contain pores of about 75 µm2. Human embryonic stem cell-derived RPCs, derived from a single pluripotent stem cell line, embed within the scaffolds. Under relatively simple differentiation conditions and after only seven days, the cells express a limited number of RGC associated genes (&betra;-III-tubulin, BRN3a, SNCG, MAP2, and THY1) at higher rates than when cultured on laminin-coated tissue culture polystyrene (TCP). Although neurite outgrowth and expression of synaptic proteins was similar between differentiated RGCs cultured on scaffolds and TCP, neurites on PGS/PCL scaffolds aligned with the orientation of the nanofibers whereas on TCP the neurites grew in more random directions.

This study provides intriguing preliminary data and raises many exciting questions that will need to be evaluated in further experimental work. Is this methodology reproducible with multiple independent ES and induced pluripotent cell lines? How do RGCs differentiated on PGC/PCL scaffolds compare to other 2D and 3D organoid-based protocols with regard to overall efficiency, developmental maturity, electrophysiological function, and RGC subtype diversity? Does intraocular transplantation within biocompatible scaffolds afford greater graft survival or more efficient retinal integration? The ability to direct neurite outgrowth is particularly valuable if RGCs specify axons that can be directed to the optic nerve head, and RGC-embedded scaffolds may be poised to help achieve this outcome. As RGC transplantation comes to an age of robust experimental study that includes functional outcomes,13-15 the benefit of RGC transplantation within scaffolds may soon become clearer.

The ability to direct neurite outgrowth is particularly valuable if RGCs specify axons that can be directed to the optic nerve head, and RGC-embedded scaffolds may be poised to help achieve this outcome

References

  1. Zhang KY, Aguzzi EA, Johnson TV. Retinal Ganglion Cell Transplantation: Approaches for Overcoming Challenges to Functional Integration. Cells. 2021;10(6).
  2. Sluch VM, Chamling X, Liu MM, et al. Enhanced Stem Cell Differentiation and Immunopurification of Genome Engineered Human Retinal Ganglion Cells. Stem Cells Translational Medicine. 2017;6(11):1972-1986.
  3. Gill KP, Hewitt AW, Davidson KC, Pebay A, Wong RC. Methods of Retinal Ganglion Cell Differentiation From Pluripotent Stem Cells. Transl Vis Sci Technol. 2014;3(4):7.
  4. Lee J, Choi SH, Kim YB, et al. Defined Conditions for Differentiation of Functional Retinal Ganglion Cells From Human Pluripotent Stem Cells. Invest Ophthalmol Vis Sci. 2018;59(8):3531-3542.
  5. Chavali VRM, Haider N, Rathi S, et al. Dual SMAD inhibition and Wnt inhibition enable efficient and reproducible differentiations of induced pluripotent stem cells into retinal ganglion cells. Scientific Reports. 2020;10(1).
  6. Rabesandratana O, Chaffiol A, Mialot A, et al. Generation of a Transplantable Population of Human iPSC-Derived Retinal Ganglion Cells. Front Cell Dev Biol. 2020;8.
  7. Ji SL, Tang SB. Differentiation of retinal ganglion cells from induced pluripotent stem cells: a review. Int J Ophthalmol. 2019;12(1):152-160.
  8. Fligor CM, Langer KB, Sridhar A, et al. Three-Dimensional Retinal Organoids Facilitate the Investigation of Retinal Ganglion Cell Development, Organization and Neurite Outgrowth from Human Pluripotent Stem Cells. Scientific Reports. 2018;8.
  9. Gasparini SJ, Llonch S, Borscht O, Ader M. Transplantation of photoreceptors into the degenerative retina: Current state and future perspectives. Progr Ret Eye Res. 2019;69:1-37.
  10. Li KJ, Zhong XF, Yang SJ, et al. HiPSC-derived retinal ganglion cells grow dendritic arbors and functional axons on a tissue-engineered scaffold. Acta Biomaterialia. 2017;54:117-127.
  11. Behtaj S, Karamali F, Masaeli E, Anissimov YG, Rybachuk M. Electrospun PGS/PCL, PLLA/PCL, PLGA/PCL and pure PCL scaffolds for retinal progenitor cell cultivation. Biochem Eng J. 2021;166.
  12. Behtaj S, Karamali F, Najafian S, et al. The role of PGS/PCL scaffolds in promoting differentiation of human embryonic stem cells into retinal ganglion cells. Acta Biomaterialia. 2021;126:238-248.
  13. Zhang KY, Tuffy C, Mertz JL, et al. Role of the Internal Limiting Membrane in Structural Engraftment and Topographic Spacing of Transplanted Human Stem Cell-Derived Retinal Ganglion Cells. Stem Cell Rep. 2021;16(1):149-167.
  14. Venugopalan P, Wang Y, Nguyen T, et al. Transplanted neurons integrate into adult retinas and respond to light. Nat Commun. 2016;7.
  15. Oswald J, Kegeles E, Minelli T, Volchkov P, Baranov P. Transplantation of miPSC/ mESC-derived retinal ganglion cells into healthy and glaucomatous retinas. Mol Ther Methods Clin Dev. 2021;21:180-198.


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