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Editors Selection IGR 22-2

Basic Science: Can stem cells restore trabecular meshwork function?

Comment by Thomas Johnson on:

86646 Adipose-derived stem cells integrate into trabecular meshwork with glaucoma treatment potential, Zhou Y; Xia X; Yang E et al., FASEB Journal, 2020; 34: 7160-7177

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Zhou et al.¹ are to be commended for their comprehensive report of human adipose-derived stem cell (ADSC) differentiation into a trabecular meshwork (TM) phenotype. As they note, reduced cellularity of TM tissue and pathological changes in extracellular structure have been documented in human glaucoma patients and suggest that restoration of normal aqueous outflow might be achieved through a cell replacement approach. This idea is not necessarily new, and the authors themselves are responsible for some important prior work in transplantation of primary human TM cells.² Of course, obtaining a scalable source of transplantable cells is necessary. Primary human TM cell isolation is both invasive in general and problematic for autologous use in glaucoma specifically. This has driven development of protocols to obtain TM cells from human induced pluripotent stem cells (iPSCs),³ for instance. The differentiation of ADSCs into TM-like cells contributes an additional potential source.

The in-vitro characterization of ADSC-TM cells was well-designed with appropriate masking, control groups, and multimodal assays. While three potential differentiation techniques were tested, two ultimately performed best in achieving: (1) expression of two TM-related genes (CHI3L1 and AQP1); (2) phagocytosis of inactive S. Aureus particles; (3) dexamethasone- induced formation of cross-linked actin networks; and (4) dexamethasone-induced upregulation of myocilin. Importantly, both protocols required primary human TM cells to achieve differentiation - one relied on non-contact co-culture exposure and the other required secreted extracellular matrix and conditioned media from human TM cells. Therefore, obtaining ADSC-TM without needing primary human TM samples will require further identification of the specific signals that drive TM differentiation.

The authors conducted in-vivo transplantation studies in which ADSC, ADSC-TM, or human fibroblasts (as a negative control) were injected intracamerally into healthy, non-immunosuppressed mice. They identified minimal inflammation and stable IOP and aqueous outflow facility following transplantation of the two ADSC types. However, there was persistent inflammation and ocular hypertension following fibroblast injection. This is purported to demonstrate maintenance of aqueous outflow physiology by ADSC-TM cells. However, this might be better characterized as a lack of IOP dysregulation following ADSC transplantation into normal eyes - i.e., while these data are consistent with lack of harm from the transplant, any benefit of treatment has yet to be shown.

While these data are consistent with lack of harm from the transplant, any benefit of treatment has yet to be shown.

On the other hand, fibroblast injection into the anterior chamber causes inflammation, TM dysfunction, and ocular hypertension (could this have a role as an experimental glaucoma model?). As the authors note in the final sentence of their discussion, 'further studies to discover the effectiveness of stem cell transplantation in an animal model of ocular hypertension are needed.' I completely agree.

The authors conclude their paper with several interesting experiments investigating the molecular pathways that might guide ADSC-TM homing, based on their qualitative observation that these cells seemed to preferentially localize to the TM when intracamerally injected. Some caution, however, is needed in interpreting these data and I think this is one area where further control experiments will be critical to the future of this work. The photoreceptor transplantation field was shaken by the 2016 discovery that the majority of purported donor cell integration actually represented an artifactual misidentification donor cells due to of donor-to-host intercellular transfer of donor cell label (i.e., material transfer).^4-6 As such, the present work would benefit from more robust methods to assure that the DiO label from injected ADSCs, ADSC-TMs, or fibroblasts was not simply transferred to or phagocytosed by endogenous host TM cells. While the authors' identification of CHI3L1 and AQP1 transcripts in the eyes of recipient mice using human-specific qPCR primers suggests that some donor cells survived at the timepoints tested, the number and location of human cells responsible for those transcripts remains unclear. As is now standard in the retinal cell transplantation field, additional controls including (1) immunohistochemical detection of human-specific antigens in the donor cells; (2) transplantation into pan XFP-expressing recipients and demonstration of XFP exclusion from purported donor cells; and/or (3) sex-mismatched donor/recipient experiments with sex-chromosomal fluorescence in situ hybridization could help clarify if this point.

In summary, this paper highlights new possibilities for IOP reduction in glaucoma through cell transplantation. However, we await confirmatory results showing that donor human ADSC-TM cells truly integrate following transplantation and additional experiments that demonstrate a beneficial therapeutic effect in an ocular hypertensive model of glaucoma.

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