Li Li

All Publications

• GFAP Mutations in Astrocytes Impair Oligodendrocyte Progenitor Proliferation and Myelination in an hiPSC Model of Alexander Disease CELL STEM CELL Li, L., Tian, E., Chen, X., Chao, J., Klein, J., Qu, Q., Sun, G., Sun, G., Huang, Y., Warden, C. D., Ye, P., Feng, L., Li, X., Cui, Q., Sultan, A., Douvaras, P., Fossati, V., Sanjana, N. E., Riggs, A. D., Shi, Y. 2018; 23 (2): 239-+

  Abstract

  Alexander disease (AxD) is a leukodystrophy that primarily affects astrocytes and is caused by mutations in the astrocytic filament gene GFAP. While astrocytes are thought to have important roles in controlling myelination, AxD animal models do not recapitulate critical myelination phenotypes and it is therefore not clear how AxD astrocytes contribute to leukodystrophy. Here, we show that AxD patient iPSC-derived astrocytes recapitulate key features of AxD pathology such as GFAP aggregation. Moreover, AxD astrocytes inhibit proliferation of human iPSC-derived oligodendrocyte progenitor cells (OPCs) in co-culture and reduce their myelination potential. CRISPR/Cas9-based correction of GFAP mutations reversed these phenotypes. Transcriptomic analyses of AxD astrocytes and postmortem brains identified CHI3L1 as a key mediator of AxD astrocyte-induced inhibition of OPC activity. Thus, this iPSC-based model of AxD not only recapitulates patient phenotypes not observed in animal models, but also reveals mechanisms underlying disease pathology and provides a platform for assessing therapeutic interventions.

  View details for DOI 10.1016/j.stem.2018.07.009

  View details for Web of Science ID 000440583900014

  View details for PubMedID 30075130

  View details for PubMedCentralID PMC6230521

• Astrocytic response mediated by the CLU risk allele inhibits OPC proliferation and myelination in a human iPSC model. Cell reports Liu, Z., Chao, J., Wang, C., Sun, G., Roeth, D., Liu, W., Chen, X., Li, L., Tian, E., Feng, L., Davtyan, H., Blurton-Jones, M., Kalkum, M., Shi, Y. 2023; 42 (8): 112841

  Abstract

  The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

  View details for DOI 10.1016/j.celrep.2023.112841

  View details for PubMedID 37494190

• Anatomical and functional maturation of the mid-gestation human enteric nervous system. Nature communications Dershowitz, L. B., Li, L., Pasca, A. M., Kaltschmidt, J. A. 2023; 14 (1): 2680

  Abstract

  Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.

  View details for DOI 10.1038/s41467-023-38293-z

  View details for PubMedID 37160892

  View details for PubMedCentralID PMC10170115

• Single-cell transcriptomic landscape of the developing human spinal cord. Nature neuroscience Andersen, J., Thom, N., Shadrach, J. L., Chen, X., Onesto, M. M., Amin, N. D., Yoon, S. J., Li, L., Greenleaf, W. J., Müller, F., Pașca, A. M., Kaltschmidt, J. A., Pașca, S. P. 2023

  Abstract

  Understanding spinal cord assembly is essential to elucidate how motor behavior is controlled and how disorders arise. The human spinal cord is exquisitely organized, and this complex organization contributes to the diversity and intricacy of motor behavior and sensory processing. But how this complexity arises at the cellular level in the human spinal cord remains unknown. Here we transcriptomically profiled the midgestation human spinal cord with single-cell resolution and discovered remarkable heterogeneity across and within cell types. Glia displayed diversity related to positional identity along the dorso-ventral and rostro-caudal axes, while astrocytes with specialized transcriptional programs mapped into white and gray matter subtypes. Motor neurons clustered at this stage into groups suggestive of alpha and gamma neurons. We also integrated our data with multiple existing datasets of the developing human spinal cord spanning 22 weeks of gestation to investigate the cell diversity over time. Together with mapping of disease-related genes, this transcriptomic mapping of the developing human spinal cord opens new avenues for interrogating the cellular basis of motor control in humans and guides human stem cell-based models of disease.

  View details for DOI 10.1038/s41593-023-01311-w

  View details for PubMedID 37095394

  View details for PubMedCentralID 8353162

• Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis NATURE CANCER Cui, Q., Yin, K., Zhang, X., Ye, P., Chen, X., Chao, J., Meng, H., Wei, J., Roeth, D., Li, L., Qin, Y., Sun, G., Zhang, M., Klein, J., Huynhle, M., Wang, C., Zhang, L., Badie, B., Kalkum, M., He, C., Yi, C., Shi, Y. 2021; 2 (9): 932-+

  Abstract

  Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here, we show that pseudouridine synthase 7 (PUS7) is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in patients with glioblastoma. PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identify PUS7 targets in GSCs through small RNA pseudouridine sequencing and show that pseudouridylation of PUS7-regulated transfer RNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identify chemical inhibitors for PUS7 and show that these compounds prevent PUS7-mediated pseudouridine modification, suppress tumorigenesis and extend the life span of tumor-bearing mice. Overall, we identify an epitranscriptomic regulatory mechanism in glioblastoma and provide preclinical evidence of a potential therapeutic strategy for glioblastoma.

  View details for DOI 10.1038/s43018-021-00238-0

  View details for Web of Science ID 000686465500003

  View details for PubMedID 35121864

  View details for PubMedCentralID PMC8809511

• Cell-Based Therapy for Canavan Disease Using Human iPSC-Derived NPCs and OPCs ADVANCED SCIENCE Feng, L., Chao, J., Tian, E., Li, L., Ye, P., Zhang, M., Chen, X., Cui, Q., Sun, G., Zhou, T., Felix, G., Qin, Y., Li, W., Meza, E., Klein, J., Ghoda, L., Hu, W., Luo, Y., Dang, W., Hsu, D., Gold, J., Goldman, S. A., Matalon, R., Shi, Y. 2020

  View details for DOI 10.1002/advs.202002155

  View details for Web of Science ID 000582778200001

• Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma SCIENCE TRANSLATIONAL MEDICINE Wang, D., Starr, R., Chang, W., Aguilar, B., Alizadeh, D., Wright, S. L., Yang, X., Brito, A., Sarkissian, A., Ostberg, J. R., Li, L., Shi, Y., Gutova, M., Aboody, K., Badie, B., Forman, S. J., Barish, M. E., Brown, C. E. 2020; 12 (533)

  Abstract

  Although chimeric antigen receptor (CAR) T cells have demonstrated signs of antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To achieve broader and more effective GBM targeting, we developed a peptide-bearing CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). We find that CLTX peptide binds a great proportion of tumors and constituent tumor cells. CAR T cells using CLTX as the targeting domain (CLTX-CAR T cells) mediate potent anti-GBM activity and efficiently target tumors lacking expression of other GBM-associated antigens. Treatment with CLTX-CAR T cells resulted in tumor regression in orthotopic xenograft GBM tumor models. CLTX-CAR T cells do not exhibit observable off-target effector activity against normal cells or after adoptive transfer into mice. Effective targeting by CLTX-CAR T cells requires cell surface expression of matrix metalloproteinase-2. Our results pioneer a peptide toxin in CAR design, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.

  View details for DOI 10.1126/scitranslmed.aaw2672

  View details for Web of Science ID 000518934500002

  View details for PubMedID 32132216

• When glia meet induced pluripotent stem cells (iPSCs). Molecular and cellular neurosciences Li, L. n., Shi, Y. n. 2020; 109: 103565

  Abstract

  The importance of glial cells, mainly astrocytes, oligodendrocytes, and microglia, in the central nervous system (CNS) has been increasingly appreciated. Recent advances have demonstrated the diversity of glial cells and their contribution to human CNS development, normal CNS functions, and disease progression. The uniqueness of human glial cells is also supported by multiple lines of evidence. With the discovery of induced pluripotent stem cells (iPSCs) and the progress of generating glial cells from human iPSCs, there are numerous studies to model CNS diseases using human iPSC-derived glial cells. Here we summarize the basic characteristics of glial cells, with the focus on their classical functions, heterogeneity, and uniqueness in human species. We further review the findings from recent studies that use iPSC-derived glial cells for CNS disease modeling. We conclude with promises and future directions of using iPSC-derived glial cells for CNS disease modeling.

  View details for DOI 10.1016/j.mcn.2020.103565

  View details for PubMedID 33068719

• Modeling neurological diseases using iPSC-derived neural cells iPSC modeling of neurological diseases CELL AND TISSUE RESEARCH Li, L., Chao, J., Shi, Y. 2018; 371 (1): 143–51

  Abstract

  Developing efficient models for neurological diseases enables us to uncover disease mechanisms and develop therapeutic strategies to treat them. Discovery of reprogramming somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the way of modeling human diseases, especially neurological diseases. Currently almost all types of neural cells, including but not limited to neural stem cells, neurons, astrocytes, oligodendrocytes and microglia, can be derived from iPSCs following developmental principles. These iPSC-derived neural cells provide valuable tools for studying neurological disease mechanisms, developing potential therapies, and deepening our understanding of the nervous system.

  View details for DOI 10.1007/s00441-017-2713-x

  View details for Web of Science ID 000419146100012

  View details for PubMedID 29079884

  View details for PubMedCentralID PMC6029980

• m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells CELL REPORTS Cui, Q., Shi, H., Ye, P., Li, L., Qu, Q., Sun, G., Sun, G., Lu, Z., Huang, Y., Yang, C., Riggs, A. D., He, C., Shi, Y. 2017; 18 (11): 2622–34

  Abstract

  RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

  View details for DOI 10.1016/j.celrep.2017.02.059

  View details for Web of Science ID 000397330000009

  View details for PubMedID 28297667

  View details for PubMedCentralID PMC5479356