Biology subjects

Eade, K. T.

Publications and source records attributed to Eade, K. T..

5 recordsLinked to original sources

bioRxiv2026

Encapsulated cell technology delivers ciliary neurotrophic factor to promote JAK/STAT-dependent photoreceptor survival in retinal degeneration

Sustained trophic factor delivery via Encapsulated Cell Technology (ECT) is a powerful new class of therapeutics with broad potential for targeted treatment. Intravitreal delivery of ciliary neurotrophic factor (CNTF) via the ECT, NT-501, is a first-in-class therapy that slows the progression of macular telangiectasia type 2 (MacTel). Despite its clinical efficacy, key questions remain regarding its mechanism of action, including whether other implant-derived factors contribute to therapeutic benefit and how optimal dosing should be determined. Resolving these issues is critical for optimizing NT-501 in MacTel and guiding the development of ECT-based therapies for other diseases. We evaluated the biological activity of implant-derived cytokines on retinal tissue, using long-term NT-501 intravitreal implants in rabbits alongside human retinal organoid (hRO) models treated with NT-501-conditioned medium (NT-501-CM). Then, using a MacTel-specific photoreceptor degeneration model in hROs, we showed NT-501-CM significantly reduced photoreceptor cell death, and this protective effect was abolished by either CNTF-neutralizing antibodies or JAK inhibitor. We also established a therapeutic dose-response relationship linking NT-501-derived CNTF levels to JAK/STAT3 activation and photoreceptor protection. These findings directly connect ECT-derived CNTF exposure with JAK/STAT3-mediated photoreceptor protection in human retinal tissue and suggest an optimal concentration range for efficacy.

pharmacology and toxicology↗

bioRxiv2026

An early CYP26A1/CRYAA progenitor-glial domain marks the presumptive macular region during human retinal development

The human macula, a high-acuity retinal region essential for central vision, emerges early in development, but the cellular basis of its regional specialisation remains incompletely resolved. Building on recent studies that identified CYP26A1-mediated retinoic acid (RA) suppression in the presumptive macula, we define a CRYAA-positive progenitor-glial compartment in the temporal human retina from post-conception week (pcw) 7 onward. Single-cell RNA sequencing, immunohistochemistry and spatial morphometry indicate that this compartment is linked to regional gliogenic maturation and later corresponds to a specialised macular Muller glial population, rather than simply reflecting uniform pan-retinal developmental timing. Spatial mapping shows that the CYP26A1-positive domain remains delimited as the surrounding retina expands. Adult tissue analysis shows that CYP26A1 expression is retained in primate macular Muller glia and in corresponding acute-zone regions of visual-streak species. These findings extend current models of CYP26A1-mediated RA modulation in human acute zone/macular development by linking the early CYP26A1 domain to a regionally specialised CRYAA-positive progenitor-glial compartment. We propose that early macular patterning includes a spatially restricted glial programme that may contribute to later regional architecture and disease vulnerability.

developmental biology↗

bioRxiv2022

Integrating human iPSC-derived macrophage progenitors into retinal organoids to generate a mature retinal microglial niche

In the retina, microglia are resident immune cells that are essential for retinal development and function. Retinal microglia play a central role in mediating pathological degeneration in diseases such as glaucoma, retinitis pigmentosa, age-related neurodegeneration, ischemic retinopathy and diabetic retinopathy. Current models of mature human retinal organoids (ROs) derived from iPS cell (hiPSC) do not contain resident microglia integrated into retinal layers. Increasing cellular diversity in ROs by including resident microglia would more accurately represent the native retina and better model diseases in which microglia play a key role. In this study, we develop a new 3D in vitro tissue model of microglia-containing retinal organoids by co-culturing ROs and hiPSC-derived macrophage precursor cells (MPCs). We optimized the parameters for successful integration of MPCs into retinal organoids. We then reproducibly integrate MPCs into ROs where they develop into mature microglia (iMG) as seen by 1) migration to the appropriate anatomical locations; 2) development of a mature resting morphology; and 3) expression of mature microglial markers. We show that while in the ROs, MPCs migrate to the equivalent of the outer plexiform layer where retinal microglia cells reside in healthy retinal tissue. While there, they develop a mature morphology characterized by small cell bodies and long branching processes which is only observed in vivo. During this maturation process these microglia cycle through an activated phase followed by a stable mature phase characterized by cell-type specific microglia markers Tmem119 and P2ry12. This co-culture system may be useful for understanding the pathogenesis of retinal diseases involving retinal microglia and for drug discovery.

cell biology↗

bioRxiv2022

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

1-Deoxysphingolipids (1-dSLs) are atypical cytotoxic sphingolipids formed through the substitution of alanine for serine in de novo sphingolipid biosynthesis. Accumulation of 1-dSLs has been linked to diseases of the eye such as diabetic retinopathy and Macular Telangiectasia Type 2 (MacTel). However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remains poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define the biological pathways that contribute to toxicity caused by the 1-dSL species, 1-deoxysphinganine (1-dSA), in human retinal organoids. Our results demonstrate that 1-dSA preferentially and differentially activates signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Muller glia within retinal organoids. Using a combination of pharmacologic inhibitors and activators, we define the roles for individual arms of the UPR in 1-dSL-mediated toxicity. We show that sustained PERK signaling through the integrated stress response (ISR) promotes 1-dSL-induced apoptosis in photoreceptors. In contrast, deficiencies in signaling through the ATF6 arm of the UPR contribute to photoreceptor toxicity. These results indicate that imbalanced signaling between the pro-apoptotic PERK/ISR and protective ATF6 arms of the UPR contributes to 1-dSL-induced photoreceptor toxicity. Further, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different signaling arms of the UPR.

cell biology↗

bioRxiv2017

Activity based checkpoints ensure circuit stability in the olfactory system

Olfactory circuits function at birth, yet are continuously remodeled through the integration of adult-born interneurons into the olfactory bulb in a manner that preserves olfactory perceptual stability throughout adult life. The mechanisms that ensure appropriate circuit stability in this dynamic context remain poorly understood. Since interneurons sculpt the excitatory output of mitral and tufted (MT) neurons to the olfactory cortex, we predicted that MT neurons might instruct interneuron wiring in the adult brain. By blocking synaptic transmission from MT neurons we show that MT neuronal activity is critical to maintain olfactory bulb integrity and interneuron survival. Blocking interneuron death uncovered a second activity-dependent checkpoint regulating dendrite branching. In contrast, cortical circuits and MT neurons remain stable in the face of these silent and degenerating olfactory circuits. These studies identify a circuit-specific role for non-sensory activity in regulating integration of neurons into the adult brain, as predicted by previous computational models.

neuroscience↗