bims-mideyd 2022-04-03 papers

Issue of 2022‒04‒03
three papers selected by
Raji Shyam
Indiana University Bloomington

Stem Cells Transl Med. 2022 Mar 31. 11(3): 269-281

Retinal Cell Transplantation, Biomaterials, and In Vitro Models for Developing Next-generation Therapies of Age-related Macular Degeneration.

Lawrence J Rizzolo, Igor O Nasonkin, Ron A Adelman.

Retinal pigment epithelium (RPE) cells grown on a scaffold, an RPE patch, have potential to ameliorate visual impairment in a limited number of retinal degenerative conditions. This tissue-replacement therapy is suited for age-related macular degeneration (AMD), and related diseases. RPE cells must be transplanted before the disease reaches a point of no return, represented by the loss of photoreceptors. Photoreceptors are specialized, terminally differentiated neurosensory cells that must interact with RPE's apical processes to be functional. Human photoreceptors are not known to regenerate. On the RPE's basal side, the RPE transplant must induce the reformation of the choriocapillaris, thereby re-establishing the outer blood-retinal barrier. Because the scaffold is positioned between the RPE and choriocapillaris, it should ideally degrade and be replaced by the natural extracellular matrix that separates these tissues. Besides biodegradable, the scaffolds need to be nontoxic, thin enough to not affect the focal length of the eye, strong enough to survive the transplant procedure, yet flexible enough to conform to the curvature of the retina. The challenge is patients with progressing AMD treasure their remaining vision and fear that a risky surgical procedure will further degrade their vision. Accordingly, clinical trials only treat eyes with severe impairment that have few photoreceptors to interact with the transplanted patch. Although safety has been demonstrated, the cell-replacement mechanism and efficacy remain difficult to validate. This review covers the structure of the retina, the pathology of AMD, the limitations of cell therapy approaches, and the recent progress in developing retinal therapies using biomaterials.

Keywords: age-related macular degeneration; biomaterials; cell transplantation; retina; retinal pigment epithelium; stem cells; tissue scaffolds

DOI: https://doi.org/10.1093/stcltm/szac001

Mol Neurodegener. 2022 Mar 28. 17(1): 25

Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications.

Todd McLaughlin, Andy Medina, Jacob Perkins, Maria Yera, Joshua J Wang, Sarah X Zhang.

BACKGROUND: The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function.METHOD: We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy.
RESULTS AND CONCLUSION: We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration.

Keywords: Age related macular degeneration; Aging; Diabetic retinopathy; Endoplasmic reticulum stress; Glaucoma; Metabolism; Retinal degeneration; Retinitis pigmentosa; Unfolded protein response

DOI: https://doi.org/10.1186/s13024-022-00528-w

Autophagy. 2022 Mar 28. 1-18

The role of FYCO1-dependent autophagy in lens fiber cell differentiation.

Shahid Y Khan, Muhammad Ali, Firoz Kabir, Chan Hyun Na, Michael Delannoy, Yinghong Ma, Caihong Qiu, M Joseph Costello, J Fielding Hejtmancik, S Amer Riazuddin.

FYCO1 (FYVE and coiled-coil domain containing 1) is an adaptor protein, expressed ubiquitously and required for microtubule-dependent, plus-end-directed transport of macroautophagic/autophagic vesicles. We have previously shown that loss-of-function mutations in FYCO1 cause cataracts with no other ocular and/or extra-ocular phenotype. Here, we show fyco1 homozygous knockout (fyco1-/-) mice recapitulate the cataract phenotype consistent with a critical role of FYCO1 and autophagy in lens morphogenesis. Transcriptome coupled with proteome and metabolome profiling identified many autophagy-associated genes, proteins, and lipids respectively perturbed in fyco1-/- mice lenses. Flow cytometry of FYCO1 (c.2206C>T) knock-in (KI) human lens epithelial cells revealed a decrease in autophagic flux and autophagic vesicles resulting from the loss of FYCO1. Transmission electron microscopy showed cellular organelles accumulated in FYCO1 (c.2206C>T) KI lens-like organoid structures and in fyco1-/- mice lenses. In summary, our data confirm the loss of FYCO1 function results in a diminished autophagic flux, impaired organelle removal, and cataractogenesis.Abbreviations: CC: congenital cataracts; DE: differentially expressed; ER: endoplasmic reticulum; FYCO1: FYVE and coiled-coil domain containing 1; hESC: human embryonic stem cell; KI: knock-in; OFZ: organelle-free zone; qRT-PCR: quantitative real-time PCR; PE: phosphatidylethanolamine; RNA-Seq: RNA sequencing; SD: standard deviation; sgRNA: single guide RNA; shRNA: shorthairpin RNA; TEM: transmission electron microscopy; WT: wild type.

Keywords: Autophagy; cataracts; lens fiber cells; organelle removal; organelle-free zone

DOI: https://doi.org/10.1080/15548627.2022.2025570