The human eye, a masterpiece of evolution, orchestrates the intricate process of vision. The retina is a tissue with a layered structure that plays a critical role in converting light signals into neural impulses interpretable by the brain. Various eye conditions such as glaucoma, retinitis pigmentosa, age‐related macular degeneration, and other retinopathies are characterized by damage or degeneration in the retina. Recent strides in organoid cultivation and advanced three‐dimensional (3D) bioengineering technologies offer promising avenues for potential therapeutic interventions. Compared to traditional two‐dimensional cell culture models, which are non‐natural and limited in accuracy, 3D models, including organoids, electrospinning constructs, microfabrication‐based scaffolds, and hydrogel systems, are more delicate, especially in recapitulating tissue architecture, offering spatial patterning, and enabling vascularization. Retinal organoids are 3D multicellular structures derived from stem cells that can mimic the retina's layered architecture and functionality. However, their inherent complexity, including the presence of multiple differentiated cell types, may not be necessary for all disease modeling applications. In contrast, engineered 3D technologies can be tailored to specific retinal diseases by incorporating only the most relevant cell types, matrix stiffness, and spatial arrangements, offering greater experimental control and reproducibility in targeted therapeutic testing. In the following paper, we will discuss organoid generation in detail. Besides retinal organoids, bioprinting is another promising avenue for regenerative medicines. We further review a suite of 3D fabrication strategies, including inkjet and laser‐assisted bioprinting, electrospun scaffolds, and hydrogel systems, and evaluate their current and potential applications in modeling retinal diseases and developing translational therapies. We will also delve into the contemporary advancements in retinal therapies, particularly emphasizing the roles and prospects of organoid and engineered 3D technologies.

Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is characterized by progressive motor neuron degeneration, leading to widespread weakness and respiratory failure. While a variety of mechanisms have been proposed as causes of this disease, a full understanding remains elusive. Electrophysiological alterations, including increased motor axon excitability, likely play an important role in disease progression. There remains a critical need for non-animal disease models that can integrate electrophysiological tools to better understand underlying mechanisms, track disease progression, and evaluate potential therapeutic interventions. This review explores the integration of electrophysiological technologies with ALS disease models. It covers cellular and clinical electrophysiological tools and their applications in ALS research. Additionally, we examine conventional animal models and highlight advancements in humanized models and 3D organoid technologies. By bridging the gap between these models, we aim to enhance our understanding of ALS pathogenesis and facilitate the development of new therapeutic strategies.

Optineurin (OPTN) is an adaptor protein that plays a crucial role in many cellular pathways, including NF-κB signaling, programmed cell death, and vesicular trafficking. OPTN dysfunction has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS). While mutations of OPTN seem to be predominantly loss-of-function in ALS, only gain-of-function mechanisms have been reported in POAG. Here, we demonstrate that OPTN knockout in the retina contributes to short-term astrogliosis, retinal ganglion cell (RGC) loss and long-term microglial activation. Moreover, OPTN loss of function does not exacerbate RGC death induced by ocular hypertension. Integrated bioinformatics and immunofluorescence analyses reveal that OPTN dysfunction leads to neuropeptide Y (NPY) downregulation and CHOP upregulation. Overexpression of wild-type OPTN in a hypertension glaucoma model prevents the RGC loss and attenuates microglial activation. Together, our findings highlight a neuroprotective role for OPTN as a key neuroimmune modulator.

Optineurin (OPTN) is a crucial component of the homeostatic pathway, playing a pivotal role in regulating a number of essential signaling pathways including NF-κB, interferon, autophagy, and vesicular trafficking. The dysfunction of OPTN has been implicated in the pathogenesis of several diseases, such as primary open angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia, and Paget’s disease of bone. Interestingly, mutations in OPTN are implicated as gain-of-function in glaucoma pathology and loss-of-function in ALS. However, the role of loss-of-function OPTN in glaucoma pathology remains unclear. Here, we demonstrate that OPTN dysfunction contributes to chronic neuroinflammation, leading to sustained RGC death, which may represent a shared pathological mechanism in both normal tension glaucoma (NTG) and high-tension glaucoma (HTG). Retinal conditioned OPTN knockout contributes to short-term astrogliosis and long-term microglia activation, with the propagation of microglia activation spreading to the optic nerve. Moreover, OPTN loss of function does not further exacerbate RGC death in the ocular hypertension mouse model induced by viscobead injection. Combined with the downregulation of OPTN in glaucoma patients, we have revealed an IOP-independent mechanism of glaucoma pathogenesis. Furthermore, we found that OPTN-driven NPY upregulation may suppress the CHOP-associated neurodegeneration. Our findings reveal a neuroprotective role for the OPTN-NPY signaling pathway, and its dysfunction promotes RGC loss in glaucoma pathology. The OPTN-NPY-mediated neuroinflammatory pathway provides a potential therapy for IOP-resistant glaucoma and highlights a druggable target for CHOP-associated neurodegeneration.

Chronic low back pain (LBP), predominantly driven by intervertebral disc degeneration (IVDD) is a major public health burden, yet the molecular mechanisms linking disc pathology to inflammation and pain remain poorly understood. Here, we identify a fibrotic, late-stage population of nucleus pulposus (NP) cells in degenerating intervertebral discs that aberrantly upregulate Colony Stimulating Factor 1 (CSF1). NP-derived CSF1 activates the CSF1 Receptor (CSF1R) on infiltrating macrophages, triggering a sustained pro-inflammatory cascade within the microenvironment. Using a murine model of disc injury, we demonstrate that either genetic ablation of Csf1r or pharmacologic inhibition with the selective CSF1R antagonist GW2580 markedly attenuates disc degeneration, confirmed by longitudinal MRI and histopathology, and significantly reduces associated neuropathic pain behaviors. These findings establish the CSF1–CSF1R axis as a central mechanistic link between fibrotic NP cell remodeling and macrophage-driven inflammation, highlighting it as a promising therapeutic target for mitigating disc degeneration and alleviating chronic LBP. One Sentence Summary: Blocking CSF1 signaling alleviates intervertebral disc degeneration and neuropathic pain