Caiwei Guo

All Publications

• Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction. Science translational medicine Guo, C., Chen, K., Vatsavayai, S., Akiyama, T., Liu, C., Zeng, Y., Sianto, O., Yang, E., Bombosch, J., Powell, R., Zhen, S., Mekhoubad, S., Morrie, R. D., Miller, G., Ilic, D., Boll, M., Parnell, E., Penzes, P., Lipstein, N., Green, E. M., Petrucelli, L., Seeley, W. W., Gitler, A. D. 2026; 18 (852): eaeb8517

  Abstract

  TAR DNA binding protein 43 (TDP-43) pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report previously unidentified TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7, and KCNQ2. Using human stem cell-derived neurons, we showed that TDP-43 reduction induces cryptic splicing and down-regulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occurred selectively in neurons with TDP-43 pathology. Suppressing individual cryptic splicing events using antisense oligonucleotides partially restored neuronal function, and combined targeting almost fully rescued the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

  View details for DOI 10.1126/scitranslmed.aeb8517

  View details for PubMedID 42234776

• KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. JCI insight Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L., Lyons, H., Molotsky, E., Bombosch, J. S., Sianto, O., Ross, J. P., Hoang, P., Zhao, L., Spencer, C., Sumner, C. J., Monje, M., Day, J. W., Gitler, A. D. 2026

  Abstract

  Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene leading to decreased SMN protein levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. SMN deficiency resulted in downregulation of kinesin heavy chain isoform 5A (KIF5A) in human neurons and in a mouse model of SMA. SMN associated with KIF5A mRNA and contributed to its stability. Reduced SMN levels impaired axon regeneration, which was rescued by KIF5A overexpression. Because KIF5A has also been connected to ALS, these findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as an SMN regulated factor. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

  View details for DOI 10.1172/jci.insight.197941

  View details for PubMedID 41885937

• TDP-43 suppression of ATP8A2 cryptic splicing implicates phosphatidylserine-driven neuroinflammation in ALS/FTD. bioRxiv : the preprint server for biology O'Connor, J. T., Loo, H. Q., Guo, C., Pickles, S., Sundali, S., Jawahar, V. M., Dickson, D. W., Bloom, A. J., Petrucelli, L., Gitler, A. D., Milbrandt, J., DiAntonio, A. 2025

  Abstract

  Inappropriate externalization of phosphatidylserine (PS) is a candidate mechanism of pathogenic neuroinflammation, a critical driver of neurodegenerative disease. ATP8A2, a flippase that maintains PS on the plasma membrane inner leaflet, is mutated in both Wabbler-lethal mice and patients with the ataxia syndrome CAMRQ4. Here, we identify ATP8A2 as a target of TDP-43 cryptic exon suppression, and demonstrate that ATP8A2 loss leads to immune-mediated neurodegeneration. ATP8A2 splicing is significantly dysregulated following TDP-43 depletion in human neurons and in brains of patients with Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In mice, Atp8a2 loss increases PS exposure and promotes neuroinflammation. Depletion of peripheral macrophages rescues motor axon degeneration and doubles Atp8a2 knockout mouse lifespan, while depletion of both peripheral macrophages and central microglia quadruples lifespan and improves coordination. Hence, ATP8A2 is a pathologically relevant TDP-43 target and inhibition of phagocytic immune cell attack against neurons is a potential treatment for patients with CAMRQ4 and ALS-FTD.

  View details for DOI 10.1101/2025.11.21.689833

  View details for PubMedID 41394670

  View details for PubMedCentralID PMC12697532

• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes. Nature neuroscience Zeng, Y., Lovchykova, A., Akiyama, T., Rayner, S. L., Maheswari Jawahar, V., Liu, C., Sianto, O., Guo, C., Calliari, A., Prudencio, M., Dickson, D. W., Petrucelli, L., Gitler, A. D. 2025

  Abstract

  In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus of neurons in the brain and spinal cord. A key function of TDP-43 has emerged as a repressor of cryptic exon inclusion during pre-mRNA splicing, but a role for TDP-43 in other RNA-processing events remains unresolved. Here we show that loss of TDP-43 from neuronal nuclei of human brain and disease-causing mutations in TDP-43 are associated with widespread changes in alternative polyadenylation (APA). Using high-resolution polyadenylation site mapping, we comprehensively defined TDP-43-regulated APA events in human stem cell-derived neurons and found that both the strength and position of TDP-43 binding influence polyA site usage. APA events caused by loss of TDP-43 impact expression of disease-relevant genes (for example, SFPQ, NEFL and TMEM106B). These findings provide evidence that, in addition to cryptic exon inclusion, APA changes are a new facet of TDP-43 pathology.

  View details for DOI 10.1038/s41593-025-02049-3

  View details for PubMedID 41120750

  View details for PubMedCentralID 3108889

• Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction. bioRxiv : the preprint server for biology Guo, C., Chen, K., Vatsavayai, S. C., Akiyama, T., Zeng, Y., Liu, C., Sianto, O., Yang, E., Bombosch, J., Powell, R., Zhen, S., Mekhoubad, S., Morrie, R. D., Miller, G., Green, E. M., Petrucelli, L., Seeley, W. W., Gitler, A. D. 2025

  Abstract

  TDP-43 pathology is a defining pathological hallmark of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major feature of TDP-43 pathology is its nuclear depletion, leading to the aberrant inclusion of cryptic exons during RNA splicing. STMN2 and UNC13A have emerged as prominent TDP-43 splicing targets, but the broader impact of TDP-43-dependent cryptic splicing on neuronal function remains unclear. Here, we report new TDP-43 splicing targets critical for membrane excitability and synaptic function, including KALRN, RAP1GAP, SYT7 and KCNQ2. Using human stem cell-derived neurons, we show that TDP-43 reduction induces cryptic splicing and downregulation of these genes, resulting in impaired excitability and synaptic transmission. In postmortem brains from patients with FTD, these cryptic splicing events occur selectively in neurons with TDP-43 pathology. Importantly, suppressing individual cryptic splicing events using antisense oligonucleotides partially restores neuronal function, and combined targeting almost fully rescues the synaptic deficit caused by TDP-43 loss. Together, our findings provide evidence that cryptic splicing in these synaptic and membrane excitability genes is not only a downstream marker but instead a direct driver of neuronal dysfunction, establishing a mechanistic link between TDP-43 pathology and neurodegeneration in ALS and FTD.

  View details for DOI 10.1101/2025.08.28.672801

  View details for PubMedID 40949955

  View details for PubMedCentralID PMC12424808

• KIF5A downregulation in spinal muscular atrophy links axonal regeneration defects with ALS. bioRxiv : the preprint server for biology Akiyama, T., Zeng, Y., Guo, C., Gautier, O., Koepke, L. S., Bombosch, J., Sianto, O., Ross, J. P., Hoang, P. T., Zhao, L. Y., Spencer, C., Monje, M., Day, J. W., Gitler, A. D. 2025

  Abstract

  Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to decreased SMN levels and motor neuron dysfunction. SMN-restoring therapies offer clinical benefit, but the downstream molecular consequences of SMN reduction remain incompletely understood. Here, we demonstrate that SMN deficiency results in downregulation of KIF5A in human neurons and in a mouse model of SMA. We provide evidence that reduced SMN levels impair axon regeneration, which is rescued by KIF5A overexpression and that the RNA-binding protein SMN functions to stabilize KIF5A mRNA. These findings provide evidence of a molecular link between SMA and ALS pathophysiology, highlighting KIF5A as a new SMN target. Our findings suggest SMN-independent interventions targeting KIF5A could represent a complementary therapeutic approach for SMA and other motor neuron diseases.

  View details for DOI 10.1101/2025.07.11.664426

  View details for PubMedID 40672150

  View details for PubMedCentralID PMC12265700

• TDP-43 nuclear loss in FTD/ALS causes widespread alternative polyadenylation changes. bioRxiv : the preprint server for biology Zeng, Y., Lovchykova, A., Akiyama, T., Liu, C., Guo, C., Jawahar, V. M., Sianto, O., Calliari, A., Prudencio, M., Dickson, D. W., Petrucelli, L., Gitler, A. D. 2024

  Abstract

  In frontotemporal dementia and amyotrophic lateral sclerosis, the RNA-binding protein TDP-43 is depleted from the nucleus. TDP-43 loss leads to cryptic exon inclusion but a role in other RNA processing events remains unresolved. Here, we show that loss of TDP-43 causes widespread changes in alternative polyadenylation, impacting expression of disease-relevant genes (e.g., ELP1, NEFL, and TMEM106B) and providing evidence that alternative polyadenylation is a new facet of TDP-43 pathology.

  View details for DOI 10.1101/2024.01.22.575730

  View details for PubMedID 38328059

  View details for PubMedCentralID PMC10849503

• Tau polarizes an aging transcriptional signature to excitatory neurons and glia ELIFE Wu, T., Deger, J. M., Ye, H., Guo, C., Dhindsa, J., Pekarek, B. T., Al-Ouran, R., Liu, Z., Al-Ramahi, I., Botas, J., Shulman, J. M. 2023; 12

  Abstract

  Aging is a major risk factor for Alzheimer's disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B signaling in neurons as a marker for cellular vulnerability. We also highlight the conservation of cell-type-specific transcriptional patterns between Drosophila and human postmortem brain tissue. Overall, our results create a resource for dissection of dynamic, age-dependent gene expression changes at cellular resolution in a genetically tractable model of tauopathy.

  View details for DOI 10.7554/eLife.85251

  View details for Web of Science ID 001071628100001

  View details for PubMedID 37219079

  View details for PubMedCentralID PMC10259480

• Rnq1! You are still dangerous, but you can be my wingman anytime. Molecular cell Guo, C., Gitler, A. D. 2022; 82 (22): 4194-4196

  Abstract

  In this issue of Molecular Cell, Gropp etal. identify how the cellular background affects whether or not the Huntington's disease protein will form toxic pathological aggregates, providing insight into selective neuronal vulnerability in neurodegenerative disease.

  View details for DOI 10.1016/j.molcel.2022.10.019

  View details for PubMedID 36400005

• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. Nature Ma, X. R., Prudencio, M., Koike, Y., Vatsavayai, S. C., Kim, G., Harbinski, F., Briner, A., Rodriguez, C. M., Guo, C., Akiyama, T., Schmidt, H. B., Cummings, B. B., Wyatt, D. W., Kurylo, K., Miller, G., Mekhoubad, S., Sallee, N., Mekonnen, G., Ganser, L., Rubien, J. D., Jansen-West, K., Cook, C. N., Pickles, S., Oskarsson, B., Graff-Radford, N. R., Boeve, B. F., Knopman, D. S., Petersen, R. C., Dickson, D. W., Shorter, J., Myong, S., Green, E. M., Seeley, W. W., Petrucelli, L., Gitler, A. D. 2022

  Abstract

  A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus of neurons in the brain and spinal cord1. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing2-4. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies5,6, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.

  View details for DOI 10.1038/s41586-022-04424-7

  View details for PubMedID 35197626

• Integrated analysis of the aging brain transcriptome and proteome in tauopathy MOLECULAR NEURODEGENERATION Mangleburg, C., Wu, T., Yalamanchili, H. K., Guo, C., Hsieh, Y., Duong, D. M., Dammer, E. B., De Jager, P. L., Seyfried, N. T., Liu, Z., Shulman, J. M. 2020; 15 (1): 56

  Abstract

  Tau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes.Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (TauWT) or a mutant form causing frontotemporal dementia (TauR406W). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy.TauWT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. TauR406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes.Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

  View details for DOI 10.1186/s13024-020-00405-4

  View details for Web of Science ID 000576854700001

  View details for PubMedID 32993812

  View details for PubMedCentralID PMC7526226

• Tau-Mediated Disruption of the Spliceosome Triggers Cryptic RNA Splicing and Neurodegeneration in Alzheimer's Disease CELL REPORTS Hsieh, Y., Guo, C., Yalamanchili, H. K., Abreha, M., Al-Ouran, R., Li, Y., Dammer, E. B., Lah, J. J., Levey, A. I., Bennett, D. A., De Jager, P. L., Seyfried, N. T., Liu, Z., Shulman, J. M. 2019; 29 (2): 301-+

  Abstract

  In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.

  View details for DOI 10.1016/j.celrep.2019.08.104

  View details for Web of Science ID 000489308800005

  View details for PubMedID 31597093

  View details for PubMedCentralID PMC6919331

• Tau Activates Transposable Elements in Alzheimer's Disease CELL REPORTS Guo, C., Jeong, H., Hsieh, Y., Klein, H., Bennett, D. A., De Jager, P. L., Liu, Z., Shulman, J. M. 2018; 23 (10): 2874–80

  Abstract

  Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer's disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms.

  View details for DOI 10.1016/j.celrep.2018.05.004

  View details for Web of Science ID 000434982000005

  View details for PubMedID 29874575

  View details for PubMedCentralID PMC6181645

• An ultra-fast and scalable quantification pipeline for transposable elements from next generation sequencing data Jeong, H., Yalamanchili, H., Guo, C., Shulman, J. M., Liu, Z. edited by Altman, R. B., Dunker, A. K., Hunter, L., Ritchie, M. D., Murray, T., Klein, T. E. WORLD SCIENTIFIC PUBL CO PTE LTD. 2018: 168-179

  Abstract

  Transposable elements (TEs) are DNA sequences which are capable of moving from one location to another and represent a large proportion (45%) of the human genome. TEs have functional roles in a variety of biological phenomena such as cancer, neurodegenerative disease, and aging. Rapid development in RNA-sequencing technology has enabled us, for the first time, to study the activity of TE at the systems level.However, efficient TE analysis tools are not yet developed. In this work, we developed SalmonTE, a fast and reliable pipeline for the quantification of TEs from RNA-seq data. We benchmarked our tool against TEtranscripts, a widely used TE quantification method, and three other quantification methods using several RNA-seq datasets from Drosophila melanogaster and human cell-line. We achieved 20 times faster execution speed without compromising the accuracy. This pipeline will enable the biomedical research community to quantify and analyze TEs from large amounts of data and lead to novel TE centric discoveries.

  View details for Web of Science ID 000461831500016

  View details for PubMedID 29218879

• Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease ACTA NEUROPATHOLOGICA COMMUNICATIONS Chouhan, A. K., Guo, C., Hsieh, Y., Ye, H., Senturk, M., Zuo, Z., Li, Y., Chatterjee, S., Botas, J., Jackson, G. R., Bellen, H. J., Shulman, J. M. 2016; 4: 62

  Abstract

  Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest that Drosophila may be useful for revealing determinants of neuronal dysfunction that precede cell loss, including synaptic changes, in the adult nervous system.

  View details for DOI 10.1186/s40478-016-0333-4

  View details for Web of Science ID 000379522500002

  View details for PubMedID 27338814

  View details for PubMedCentralID PMC4918017

• Transplantation of Human Neural Progenitor Cells Expressing IGF-1 Enhances Retinal Ganglion Cell Survival PLOS ONE Ma, J., Guo, C., Guo, C., Sun, Y., Liao, T., Beattie, U., Lopez, F. J., Chen, D., Lashkari, K. 2015; 10 (4): e0125695

  Abstract

  We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma.

  View details for DOI 10.1371/journal.pone.0125695

  View details for Web of Science ID 000353711600158

  View details for PubMedID 25923430

  View details for PubMedCentralID PMC4414591