About

Claire H. Mitchell, Ph.D., is a Professor of Anatomy & Cell Biology at the University of Pennsylvania's Perelman School of Medicine. Her research is concerned with the basic physiological mechanisms that interfere with the survival of neurons, astrocytes, and epithelial cells as we age. She is affiliated with the Graduate Groups in Pharmacology, Neuroscience, and Cell and Molecular Biology. Dr. Mitchell's work focuses on understanding cellular and molecular processes related to neuroinflammation, autophagy, and cell survival, with particular attention to mechanisms involving microglial activation, endolysosomal pathways, and viral infections in ocular and neural tissues.

Research topics

• Medicine
• Biology
• Neuroscience
• Cell biology
• Computer Science
• Pharmacology
• Immunology
• Computational biology
• Internal medicine
• Genetics
• Pathology
• Anesthesia
• Biochemistry
• Surgery

Selected publications

• PLGA nanoparticles restore acidic pH and degradative function to compromised lysosomes with Cy3-labeling providing enhanced tracking to lysosomes

  American Journal of Physiology-Cell Physiology · 2026-01-14

  articleSenior author

  Tools that restore acidic pH in compromised lysosomes can enhance autophagy and waste clearance in degenerative disorders characterized by excessive accumulation. Here, we describe the synthesis of lysosome-targeted nanoparticles composed of poly(d,l-lactide-co-glycolide) (PLGA) polymers covalently bound to the fluorescent dye Cyanine3 amine (Cy3). These Cy3-PLGA nanoparticles enable precise tracking of lysosomal delivery and demonstrate sustained long-term retention within lysosomes, supporting their potential for future applications aimed at restoring lysosomal pH in aging and degenerating diseases.

  PublisherDOI

• Sustained Lysosomal Delivery of Enhanced Cy3-Labeled Acid Nanoparticles Restores Lysosomal pH in Retinal Pigment Epithelial Cells and Astrocytes

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-17

  preprintOpen accessSenior author

  Abstract Lysosomal pH is frequently elevated in age-dependent neurodegenerations like Age-related Macular Degeneration (AMD), Alzheimer’s Disease (AD), and Parkinson’s Disease (PD). Tools that restore lysosomal pH to an optimal acidic range could enhance enzymatic degradation and reduce waste accumulation. Acidic nanoparticles offer a promising strategy for restoring lysosomal function, but accurate tracking of organelle delivery and long-term retention is needed to optimize dosage. To improve detection and enhance delivery, nanoparticles were synthesized from Poly(D,L-lactide-co-glycolide) (PLGA) polymers covalently linked to the fluorescent Cyanine3 amine (Cy3) probe. Nanoparticle concentration and loading times were optimized to achieve >90% delivery to lysosomes in cultured induced pluripotent stem cell-derived retinal pigment epithelial (iPS-RPE) cells. Uptake was heterogeneous, varying between adjacent cells. Once loaded into lysosomes, the nanoparticles were stably retained, with no detectable changes in concentration, distribution, or size for at least 28 days. iPS-RPE cells internalized more nanoparticles than the ARPE-19 cell line or mouse optic nerve head astrocyte cultures. Functionally, PLGA nanoparticles restored an acidic pH and cathepsin D levels in compromised lysosomes. In summary, Cy3-PLGA nanoparticles enabled improved tracking and long-term delivery to lysosomes, supporting future in vivo applications to restore lysosomal pH in aging and degenerating tissues. Graphical Abstract Increased lysosomal pH reduces degradative enzyme efficiency and contribute to age-dependent neurodegeneration. This study describes synthesis of nanoparticles to restore an acidic lumen and degradative function. Nanoparticles were optimized for lysosomal delivery to astrocytes and iPS-derived retinal pigmented epithelial (RPE) cells. The fluorescent marker Cy3 was covalently bound to polymers for improved tracking to lysosomes. Particles were stably retained inside the lysosomal lumen for at least 28 days. Nanoparticles restored pH to compromised lysosomes to baseline levels and increased active Cathepsin D. The improved design will aid in vivo tracking and repair in models where lysosomal alkalinization contributes to pathology. Created in BioRender. Mitchell, C. (2025) https://BioRender.com/8hvj96m . New and Noteworthy Tools that restore acidic pH in compromised lysosomes can enhance autophagy and waste degradation in degenerative disorders marked by excessive accumulation. Here, we describe the novel synthesis of lysosome-targeted nanoparticles composed of PLGA polymers covalently bound to Cy3 fluorescent dye. These Cy3-PLGA nanoparticles enabled improved tracking of lysosomal delivery and demonstrated sustained long-term retention within lysosomes, supporting their potential for future applications to restore lysosomal pH in aging and degenerating tissues.

  PublisherOA PDFDOI

• Acidic Nanoparticles Prevent <scp>HIV</scp> Pre‐Exposure Prophylaxis (<scp>PrEP</scp>)‐Induced Oligodendrocyte Impairments by Restoring Lysosomal <scp>pH</scp> in Adolescent Models

  Glia · 2025-07-17 · 2 citations

  articleOpen access

  A disproportionate percentage of adolescents are diagnosed with human immunodeficiency virus (HIV) in the United States each year. Preexposure prophylaxis (PrEP), an antiretroviral regimen, is effective at preventing the transmission of HIV to adolescents at substantial risk for acquiring HIV. However, other select antiretrovirals have been shown to cause white matter deficits in experimental models. Adolescents taking PrEP are uniquely vulnerable to myelin impairments as the adolescent brain undergoes high rates of myelination. Here, we report that PrEP significantly reduced oligodendrocyte maturation in adolescent rats. Furthermore, cultures of primary rat oligodendrocyte progenitors treated with PrEP showed inhibited oligodendrocyte differentiation through deacidification of lysosomes resulting in lysosomal accumulation of myelin proteins. Acidic nanoparticle co-administration with PrEP prevented PrEP-induced oligodendrocyte maturation impairments both in vivo and in vitro. These studies suggest uninfected adolescents are vulnerable to PrEP-induced oligodendrocyte impairments and identify maintenance of lysosome pH as a critical factor in antiretroviral design.

  PublisherOA PDFDOI

• Priming and release of cytokine IL-1β in microglial cells from the retina

  Experimental Eye Research · 2025-01-21 · 12 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Homologous recombination deficiency in unselected cases of high-grade ovarian carcinoma

  Journal of Medical Genetics · 2025-08-14

  article
  PublisherDOI

• Piezo1 and Piezo2 channels in retinal ganglion cells and the impact of Piezo1 stimulation on light-dependent neural activity

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-25 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Piezo channels are associated with neuropathology in diseases like traumatic brain injury and glaucoma, but pathways linking tissue stretch to aberrant neural signaling remain unclear. The present study demonstrates that Piezo1 activation increases action potential frequency in response to light and the spontaneous dark signal from mouse retinal explants. Piezo1 stimulation was sufficient to increase cytoplasmic Ca 2+ in soma and neurites, while stretch increased spiking activity in current clamp recordings from of isolated retinal ganglion cells (RGCs). Axon-marker beta-tubulin III colocalized with both Piezo1 and Piezo2 protein in the mouse optic nerve head, while RGC nuclear marker BRN3A colocalized with Piezo channels in the soma. Piezo1 was also present on GFAP-positive regions in the optic nerve head and colocalized with glutamine synthetase in the nerve fiber layer, suggesting expression in optic nerve head astrocytes and Müller glia end feet, respectively. Human RGCs from induced pluripotent stem cells also expressed Piezo1 and Piezo2 in soma and axons, while staining patterns in rats resembled those in mice. mRNA message for Piezo1 was greatest in the RPE/choroid tissue, while Piezo2 levels were highest in the optic nerve, with both channels also expressed in the retina. Increased expression of Piezo1 and Piezo2 occurred both 1 and 10 days after a single stretch in vivo; this increase suggests a potential role in rising sensitivity to repeated nerve stretch. In summary, Piezo1 and Piezo2 were detected in the soma and axons of RGCs, and stimulation affected the light-dependent output of RGCs. The rise in RGCs excitability induced by Piezo stimulation may have parallels to the early disease progression in models of glaucoma and other retinal degenerations. Highlights Activation of Piezo1 excites retinal ganglion cells, paralleling the early neurodegenerative progression in glaucoma mouse models and retinal degeneration. Piezo1 and Piezo2 were expressed in axons and soma of retinal ganglion cells in mice, rats, and human iPSC-RGCs. Functional assays confirmed Piezo1 in soma and neurites of neurons. Sustained elevation of Piezo1 and Piezo2 occurred after a single transient stretch may enhance damage from repeated traumatic nerve injury. Abstract Figure Graphical abstract Piezo1 and Piezo2 channels in retinal ganglion cells and the impact of Piezo1 stimulation on light-dependent neural activity. Puttipong Sripinun, Lily P. See, Sergei Nikonov, Venkata Ramana Murthy Chavali, Vrathasha Vrathasha, Jie He, Joan M. O’Brien, Jingsheng Xia, Wennan Lu, Claire H. Mitchell*. Activation of Piezo channels through mechanical or pharmacological stimulation leads to an influx of Ca 2+ and other cations into RGCs, depolarizing the membrane and increasing the action potential frequency to modulate the visual signal. Created with Biorender.com

  PublisherOA PDFDOI

• Increased Pan-Type, A1-Type, and A2-Type Astrocyte Activation and Upstream Inflammatory Markers Are Induced by the P2X7 Receptor

  International Journal of Molecular Sciences · 2024-08-13 · 11 citations

  articleOpen accessSenior authorCorresponding

  This study asked whether the P2X7 receptor was necessary and sufficient to trigger astrocyte polarization into neuroinflammatory activation states. Intravitreal injection of agonist BzATP increased gene expression of pan-astrocyte activation markers Gfap, Steap4, and Vim and A1-type astrocyte activation markers C3, Serping1, and H2T23, but also the Cd14 and Ptx3 genes usually associated with the A2-type astrocyte activation state and Tnfa, IL1a, and C1qa, assumed to be upstream of astrocyte activation in microglia. Correlation analysis of gene expression suggested the P2X7 receptor induced a mixed A1/A2-astrocyte activation state, although A1-state genes like C3 increased the most. A similar pattern of mixed glial activation genes occurred one day after intraocular pressure (IOP) was elevated in wild-type mice, but not in P2X7-/- mice, suggesting the P2X7 receptor is necessary for the glial activation that accompanies IOP elevation. In summary, this study suggests stimulation of the P2X7R is necessary and sufficient to trigger the astrocyte activation in the retina following IOP elevation, with a rise in markers for pan-, A1-, and A2-type astrocyte activation. The P2X7 receptor is expressed on microglia, optic nerve head astrocytes, and retinal ganglion cells (RGCs) in the retina, and can be stimulated by the mechanosensitive release of ATP that accompanies IOP elevation. Whether the P2X7 receptor connects this mechanosensitive ATP release to microglial and astrocyte polarization in glaucoma remains to be determined.

  PublisherOA PDFDOI

• Fluorescent identification of axons, dendrites and soma of neuronal retinal ganglion cells with a genetic marker as a tool for facilitating the study of neurodegeneration

  FASEB BioAdvances · 2024-12-16 · 1 citations

  articleOpen accessSenior authorCorresponding

  Abstract This study characterizes a fluorescent Slc17a6 ‐tdTomato neuronal reporter mouse line with strong labeling of axons throughout the optic nerve, of retinal ganglion cell (RGC) soma in the ganglion cell layer (GCL), and of RGC dendrites in the inner plexiform layer (IPL). The model facilitated assessment of RGC loss in models of degeneration and of RGC detection in mixed neural/glial cultures. The tdTomato signal showed strong overlap with &gt;98% cells immunolabeled with RGC markers RBPMS or BRN3A, consistent with the ubiquitous presence of the vesicular glutamate transporter 2 (VGUT2, SLC17A6) in all RGC subtypes. There was no cross‐labeling of ChAT‐positive displaced amacrine cells in the GCL, although some signal emanated from the outer plexiform layer, consistent with horizontal cells. The fluorescence allowed rapid screening of RGC loss following optic nerve crush and intraocular pressure (IOP) elevation. The bright fluorescence also enabled non‐invasive monitoring of extensive neurite networks and neuron/astrocyte interactions in culture. Robust Ca 2+ responses to P2X7R agonist BzATP were detected from fluorescent RGCs using Ca 2+ ‐indicator Fura‐2. Fluorescence from axons and soma was detected in vivo with a confocal scanning laser ophthalmoscope (cSLO); automatic RGC soma counts enhanced through machine learning approached the numbers found in retinal wholemounts. Controls indicated no impact of Slc17a6 ‐tdTomato expression on light‐dependent neuronal function as measured with a microelectrode array (MEA), or on retinal structure as measured with optical coherence tomography (OCT). In summary, the bright fluorescence in axons, dendrites and soma of ~all RGCs in the Slc17a6 ‐tdTomato reporter mouse may facilitate the study of RGCs.

  PublisherOA PDFDOI

• Fluorescent identification of axons, dendrites and soma of neuronal retinal ganglion cells with a genetic marker as a tool for facilitating the study of neurodegeneration

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-25 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract This study characterizes a fluorescent Slc17a6 -tdTomato neuronal reporter mouse line offering strong labeling in axons throughout the optic nerve, dendrites and soma in 99% of retinal ganglion cells (RGCs). The model facilitates neuronal assessment ex vivo with wholemounts quantified to show neurodegeneration following optic nerve crush or elevated IOP as related to glaucoma, in vitro with robust Ca 2+ responses to P2X7 receptor stimulation in neuronal cultures, and in vivo using a confocal scanning laser ophthalmoscope (cSLO). While the tdTomato signal showed strong overlap with RGC markers, BRN3A and RBPMS, there was no cross-labeling of displaced amacrine cells in the ganglion cell layer. Controls indicated no impact of Slc17a6 -tdTomato expression on light-dependent neuronal function, as determined with a microelectrode array (MEA), or on structure, as measured with optical coherence tomography (OCT). In summary, this novel neuronal reporter mouse model offers an effective means to increase the efficiency for real-time, specific visualization of retinal ganglion cells. It holds substantial promise for enhancing our understanding of RGC pathology in glaucoma and other diseases of the optic nerve, and could facilitate the screening of targeted therapeutic interventions for neurodegeneration. Abstract Figure Graphical abstract. Fluorescent identification of axons, dendrites and soma of neuronal retinal ganglion cells with a genetic marker as a tool for facilitating the study of neurodegeneration. Puttipong Sripinun, Wennan Lu, Sergei Nikonov, Suhani Patel, Sarah Hennessy, Claire H. Mitchell*. This study delves into a new mouse model, featuring a fluorescent Slc17a6 -tdTomato neuronal reporter. This model effectively labels axons in the optic nerve, as well as dendrites and soma in 99% of retinal ganglion cells (RGCs). This allows for both in vitro and in vivo assessment of neurodegeneration, offering a practical tool for real-time, precise visualization of RGCs, with potential applications in various fields of neuroscience and neurology. Created by Biorender.com .

  PublisherOA PDFDOI

• Retinal microglial cells increase expression and release of IL-1β when exposed to ATP

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-06-26 · 1 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Cytokine IL-1β is an early component of inflammatory cascades, with both priming and activation steps required before IL-1β release. Here, the P2X7 receptor (P2X7R) for ATP was shown to both prime and release IL-1β from retinal microglial cells. Isolated retinal microglial cells increased expression of Il1b when stimulated with endogenous receptor agonist extracellular ATP; ATP also rapidly downregulated expression of microglial markers Tmem119 and Cd206. Changes to all three genes were reduced by specific P2X7R antagonist A839977, implicating the P2X7R. Microglial cells expressed the P2X7R on ramifications and responded to receptor agonist BzATP with robust and rapid rises in intracellular Ca 2+ . BzATP increased expression of IL-1β protein colocalizing with CX3CR1-GFP in retinal wholemounts consistent with microglial cells. ATP also triggered release of IL-1β from isolated retinal microglia into the bath; release was inhibited by A839977 and induced by BzATP, supporting a role for the P2X7R in release as well as priming. The IL-1β release triggered by ATP was substantially greater from microglial cells compared to astrocytes from the optic nerve head region. Il1b expression was increased by a transient rise in intraocular pressure and Il1b levels remained elevated 10 days after a single IOP elevation. In summary, this study suggests the P2X7 receptor can both prime IL-1β levels in microglial cells and trigger its release. The P2Y12R was previously identified as a chemoattractant for retinal microglia, suggesting the recruitment of the cells towards the source of released extracellular ATP could position microglia for P2X7R receptor, enabling both priming and release of IL-1β.

  PublisherOA PDFDOI

Recent grants

• Purines and the health of retinal ganglion cells

  NIH · $6.7M · 2005–2025

• Approaches to enhance lysosomal function in RPE cells

  NIH · $5.3M · 2002–2023

• P30 Core Grant For Vision Research

  NIH · $15.6M · 1997–2029

Frequent coauthors

• Wennan Lu

  California University of Pennsylvania

  73 shared

• Alan M. Laties

  University of Pennsylvania

  66 shared

• Jason Lim

  37 shared

• David Reigada

  University College London

  27 shared

• Jonathan M. Beckel

  University of Pittsburgh

  27 shared

• Sonia Guha

  Birla Institute of Technology and Science, Pilani

  24 shared

• Néstor Gómez

  19 shared

• Keith E. Campagno

  University of Pennsylvania

  18 shared

Labs

• Mitchell LabPI