About

Hongjun Song, Ph.D., is the David J. Mahoney Professor of Neurological Sciences in the Department of Neuroscience at the Perelman School of Medicine, University of Pennsylvania. His research focuses on two core topics: neural stem cell regulation and neurogenesis in the developing and adult mammalian brain, and epigenetic and epitranscriptomic mechanisms and their functions in the mammalian nervous system. His laboratory investigates how these processes influence neural function and addresses how dysfunction in these mechanisms may be involved in brain disorders. Dr. Song's work contributes to understanding the molecular and cellular basis of neurogenesis, neural circuitry, and brain disease, with a particular emphasis on epigenetic modifications such as m(6)A methylation and their roles in neural stem cell behavior and neurodevelopment.

Research topics

• Biology
• Neuroscience
• Cell biology
• Genetics
• Computer Science
• Medicine
• Pharmacology
• Chemistry
• Internal medicine
• Zoology
• Oncology
• Psychiatry
• Nanotechnology
• Computational biology
• Physics
• Biophysics
• Biochemistry
• Immunology
• Surgery
• Cancer research
• Virology
• Psychology

Selected publications

• CNSC-24. A CHOLINERGIC NEURON-TO-TUMOR CIRCUIT ENHANCES HUMAN GLIOBLASTOMA PROGRESSION VIA SYNAPTIC AND PARACRINE MECHANISMS

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract Neuronal influences on malignant brain tumor pathogenesis and progression have been increasingly recognized in the central nervous system. In glioblastoma (GBM), mainly glutamatergic inputs have been identified, and so far, they have largely been studied in the context of interspecies xenotransplantation models. We and others have recently leveraged viral tools, such as rabies virus-based retrograde tracing, to define brain-wide connectivity of GBM, which suggested the potential for GBM to receive projections from diverse neuronal subtypes, including modulatory neurons. Here, we explored the cholinergic neuron-to-glioma circuit in in vivo and all-human models to elucidate the impact of cholinergic neuronal activity on GBM biology. In mice, we leveraged electron microscopy to provide structural evidence for a basal forebrain cholinergic neuron (BFCN)-to-GBM synapse. Stimulation of BFCNs via chemogenetic approaches increased tumor cell proliferation. We further found that CHRM3 mediates the effects of BFCNs on GBM proliferation by either overexpressing CHRM3, whose specific activation increased proliferation, or knocking down CHRM3 in tumor cells, which extended mouse survival. We also developed a co-culture system employing patient-derived glioblastoma organoids and human induced pluripotent stem cell (hiPSC)-derived cholinergic neurons. In this system, we provided evidence of structural human cholinergic synaptic inputs onto GBM cells via trans-monosynaptic tracing and electron microscopy and functional synaptic interactions through the CHRM3 receptor via calcium imaging. Deep single-cell RNA sequencing of co-cultures compared to GBM monocultures further revealed shifts in tumor transcriptional profiles toward a more proliferative state, with contributions from both diffusible factors and direct contacts. Finally, pharmacological blockade of cholesterol biosynthetic pathways attenuated these effects, suggesting that lipid metabolism at least partially mediates the pro-proliferative effects of cholinergic neurons on GBM. Collectively our findings uncover a cholinergic circuit that drives GBM progression via contact-dependent and independent programs, highlighting a previously underappreciated modulatory pathway for GBM.

  PublisherOA PDFDOI

• TMOD-20. Growth rates of patient-derived tumor organoids reflect glioblastoma patients’ heterogeneity in survival

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract The generation of patient-derived glioblastoma explant organoids (GBOs) is a recent advancement in patient-focused research. Much like their parent tumors, GBOs exhibit heterogeneity in growth rate and cellular composition. As interest in their pre-clinical potential grows, we set out to determine whether GBOs may be functionally representative of tumor progression in patients. Following a protocol detailed by Jacob and colleagues in 2020, we established a GBO biobank. GBOs were imaged periodically throughout their culture and tracked using a custom Fiji macro, which allowed rapid analysis of GBO size and shape over weeks of culture. GBO roundness at 1 week of culture was found to be indicative of GBO viability and future yield. Viable GBO cultures demonstrated large variations in growth rate which were consistent between fresh and biobanked samples. Stratification of patients by GBO growth rate revealed that those with slow-growing GBOs experienced double the median overall survival time compared to patients with fast- growing GBOs (26.8 and 13 months respectively). While no differences were observed in overall viability, non-malignant populations or metabolic activity, numerous genes were found to be differentially expressed between slow and fast GBO groups. Most intriguingly, cell cycle genes were found to be comparatively upregulated in matched “slow” tumor, but the reverse was true following culture as GBOs, with upregulated cell cycle genes reflecting the increased growth rates of fast GBOs. The transcriptional differences were not found to correspond with the observed survival differences in the patient groups, suggesting that fast-growing GBOs represent a more plastic and adaptable subtype, able to thrive in in vitro conditions, a property that correlates with increased adaptation to therapeutic stress and resistance to therapy.

  PublisherOA PDFDOI

• Development and Characterization of a Primary Patient Tumor Tissue-Derived Skull-Base Chordoma Organoid Model

  Journal of Neurological Surgery Part B Skull Base · 2025-02-01

  article
  PublisherDOI

• Targeting G9a-m6A translational mechanism of SARS-CoV-2 pathogenesis for multifaceted therapeutics of COVID-19 and its sequalae

  UNC Libraries · 2025-05-22

  articleOpen access
  PublisherDOI

• m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice

  Cell stem cell · 2025-03-19 · 12 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Bioengineering tools for next-generation neural organoids

  Current Opinion in Neurobiology · 2025-03-24 · 7 citations

  reviewOpen access

  Human stem cell-derived neural organoids were recently introduced as powerful in vitro 3D experimental model systems that innately undergo critical steps of organogenesis in culture and exhibit molecular, cellular, and structural features similar to the fetal human nervous system. These organoids have yielded new insights into human neurodevelopment and associated disorders. However, neural organoids have some crucial limitations that arise from the loosely controlled conditions for their development, an inability to maintain their spatial orientation in culture and a lack of technologies for taking long-term measurements on their morphology and electrical activity. Here, we review recent progress in using bioengineering methods to improve neural organoid formation and analysis by leveraging microfabrication, biomaterials, 3D printing, and flexible electrodes. We discuss how the applications of each technique can help to address critical limitations with standard neural organoid models. We conclude with a perspective on future applications of bioengineered next-generation neural organoids.

  PublisherDOI

• Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes

  UNC Libraries · 2025-10-17

  articleOpen access1st authorCorresponding
  PublisherDOI

• Comparative molecular landscapes of immature neurons in the mammalian dentate gyrus across species reveal special features in humans

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-17

  preprintOpen accessSenior authorCorresponding

  Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine learning-augmented analysis of published single-cell RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs, and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.

  PublisherOA PDFDOI

• W51. PATIENT-SPECIFIC SETD1A MUTATIONS IMPAIR NEURONAL DIFFERENTIATION AND FUNCTION IN HUMAN CORTICAL ORGANOIDS

  European Neuropsychopharmacology · 2025-10-01

  article
  PublisherDOI

• Bioaccumulation and trophic transfer of PAHs in the Yellow River Estuary food web: A fugacity-based model for ecological and human health risk assessment

  Marine Pollution Bulletin · 2025-12-08 · 1 citations

  article
  PublisherDOI

Recent grants

• Epigenetic regulation of neurogenesis

  NIH · $8.5M · 2016–2021

• NIH Grant R33MH087874

  NIH · $805k · 2015

• Continuous Neurogenesis in the Mammalian Hippocampus

  NIH · $6.0M · 2020–2028

• NIH Grant U19MH106434

  NIH · $28.3M · 2022

• NIH Grant R21NS093772

  NIH · $446k · 2018

Frequent coauthors

• Guo‐li Ming

  1053 shared

• Kimberly M. Christian

  University of Pennsylvania

  149 shared

• Junjie U. Guo

  Affiliated Hospital of Qingdao University

  124 shared

• Ki‐Jun Yoon

  Korea Advanced Institute of Science and Technology

  110 shared

• Yijing Su

  95 shared

• Fadi Jacob

  Emory University

  93 shared

• Chun Zhong

  79 shared

• Kurt A. Sailor

  Institut Pasteur

  74 shared

Labs

• Song LabPI

Education

• B.S., Biology

  Peking University, P.R. China

  1992

• M.A., Biology

  Columbia University, New York

  1995

• Ph.D., Biology

  University of California at San Diego, La Jolla

  1998