About

Xuyu Qian, PhD, is an Assistant Professor of Pediatrics (Neurology) at the Children's Hospital of Philadelphia and a faculty member at the Center for Brain Research in Development, Genetics, and Engineering (BRIDGE). His research focuses on understanding the development and diseases of the human cerebral cortex using human-centric approaches. Dr. Qian pioneered the development of human pluripotent stem cell-derived brain organoids and their application as disease models. He also utilizes single-cell spatial transcriptomics to analyze the developing human cortex, uncovering fundamental insights into the formation and specification of distinct cortical layers and areas. By integrating organoid models, spatial omics, and human genetics, Dr. Qian aims to decode healthy developmental programs and identify the genetic and cellular disruptions that lead to diseases, paving the way for advanced therapeutic strategies.

Research topics

• Biology
• Cell biology
• Neuroscience
• Genetics
• Nanotechnology

Selected publications

• Toward Computationally Complete Spatial Omics

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-05

  articleOpen access

  Multimodal spatial omics has transformed biology by mapping molecular complexity within intact tissues, yet current technologies remain limited in the number of modalities measured simultaneously and often produce lower-quality data than single-modality assays. We present COSIE, a computational framework that generates high-resolution, multilayered molecular landscapes across tissue sections, individuals, and platforms. COSIE integrates histology, epigenome, transcriptome, proteome, and metabolome into a unified representation. Applied to 12 datasets spanning 10 spatial technologies, eight modalities, and nine tissue types, ranging from thousands of spots to millions of cells, COSIE outperforms existing methods. It resolves tissue structures, enhances noisy measurements, predicts unmeasured modalities, and captures dynamic processes. In human tumors, COSIE identifies invasive subregions linked to clinical outcomes and predicts spatial gene expression in TCGA samples using only histology images. By transforming fragmented data into comprehensive spatial maps, COSIE advances computationally complete spatial omics and the creation of digital tissue twins for biomedicine.

  PublisherDOI

• Overcoming diffusion limits to advance brain organoids

  Neural Regeneration Research · 2026-01-27

  articleOpen access1st authorCorresponding
  PublisherDOI

• Pannexin-1 channel activity regulates neurogenesis and cell survival in the developing cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-09 · 1 citations

  articleOpen access

  Abstract Mutations in genes encoding a range of ion-conducting proteins disrupt development of the cerebral cortex in humans, often causing polymicrogyria (PMG), yet how ion conduction guides the development of cortical architecture is not clear. Here, we describe three individuals with brain malformations including PMG and microcephaly in whom de novo , missense mutations were identified in PANX1 – encoding an ATP and ion conducting channel. We show that these PMG-associated PANX1 mutations (p.D14H, p.M37R, and p.N338T) disrupt normal glycosylation and confer gain-of-function with respect to ATP release and channel conductance. In vivo modeling of PANX1 mutant forms in cortical progenitor cells demonstrated disrupted cell migration and cell fate, including excess cell death in both mice and ferret models. Modeling the N338T allele in induced pluripotent stem cell (iPSC)-derived neurons further revealed how conductance changes lead to functional consequences of increased excitability and synchronicity. Our results show that normal PANX1 function contributes to cortical structure through regulation of ion conductance and ATP release and provides insight into how these processes influence corticogenesis and cytoarchitecture more broadly.

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• Author Correction: Resolving tissue complexity by multimodal spatial omics modeling with MISO

  Nature Methods · 2025-01-24 · 3 citations

  erratumOpen access
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• Resolving tissue complexity by multimodal spatial omics modeling with MISO

  Nature Methods · 2025-01-15 · 52 citations

  articleOpen access
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• Author Correction: Resolving tissue complexity by multimodal spatial omics modeling with MISO

  Nature Methods · 2025-03-06 · 3 citations

  erratumOpen access
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• Transcriptomic Convergence and the Female Protective Effect in Autism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-22 · 6 citations

  preprintOpen access

  ABSTRACT Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by deficits in social communication as well as restricted and/or repetitive behaviors. ASD is highly heritable 1 , with a complex genetic architecture: large-scale studies have identified dosage-altering copy number variants (CNV) and single nucleotide variants (SNV) that implicate hundreds of genes as individually rare causes of ASD (ASD genes) 2–4 , with common variation at multiple loci also contributing substantially to risk 5 . Understanding how disruptions to these functionally diverse genes lead to the shared core features of ASD remains a major challenge 6 . Moreover, ASD is three- to four-fold more common in males than females 7,8 , and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males 9–13 , but the biological basis of this “female protective effect” (FPE) is unknown 14,15 . Here we show that individual perturbations of 18 ASD genes converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST , that drive this transcriptomic convergence in ASD. Furthermore, the X-linked transcription factor ZFX , which is expressed from both the active and the “inactive” X chromosomes in females 16 , emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.

  PublisherDOI

• Xuyu Qian: Understanding human brain development and diseases using human-based approaches

  Genomic psychiatry : · 2025-07-08 · 1 citations

  articleOpen access1st authorCorresponding

  In this illuminating Genomic Press Interview, Dr. Xuyu Qian, a visionary neuroscientist whose groundbreaking spatial transcriptomics research promises to revolutionize our understanding of human brain development at unprecedented single-cell resolution, shares his remarkable path from an art-infused childhood in Nanjing to becoming a Forbes 30 Under 30 laureate and pioneering force in brain organoid technology. As the newly minted Assistant Professor at the University of Pennsylvania and Children's Hospital of Philadelphia, Dr. Qian has transformed our understanding of human cerebral cortex formation through his innovative fusion of spatial transcriptomics and organoid models. His landmark work, recently published in Nature (2025), leveraged state-of-the-art MERFISH technology to analyze over 18 million single cells, thereby redefining our understanding of the emergence of cortical layers and specialized brain regions during fetal development. This breakthrough builds upon his earlier revolutionary development of brain organoid protocols, now cited over 2,000 times and instrumental in shaping CDC guidelines for the prevention of Zika virus. Throughout this candid conversation, Dr. Qian reveals how the anime series Evangelion sparked his passion for biotechnology, explores his generous collaborative philosophy that has led to numerous discoveries, and articulates his commitment to human-centric approaches for decoding neurodevelopmental disorders. His distinctive combination of scientific excellence, creative vision, and infectious enthusiasm establishes him as one of neuroscience's most promising emerging leaders, destined to unravel the fundamental mysteries of human brain development and disease.

  PublisherDOI

• Spatial transcriptomics reveals human cortical layer and area specification

  Nature · 2025-05-14 · 46 citations

  articleOpen access1st authorCorresponding

  Abstract The human cerebral cortex is composed of six layers and dozens of areas that are molecularly and structurally distinct 1–4 . Although single-cell transcriptomic studies have advanced the molecular characterization of human cortical development, a substantial gap exists owing to the loss of spatial context during cell dissociation 5–8 . Here we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) 9 , augmented with deep-learning-based nucleus segmentation, to examine the molecular, cellular and cytoarchitectural development of the human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing more than 18 million single cells, spans eight cortical areas across seven developmental time points. We uncovered the early establishment of the six-layer structure, identifiable by the laminar distribution of excitatory neuron subtypes, 3 months before the emergence of cytoarchitectural layers. Notably, we discovered two distinct modes of cortical areal specification during mid-gestation: (1) a continuous, gradual transition observed across most cortical areas along the anterior–posterior axis and (2) a discrete, abrupt boundary specifically identified between the primary (V1) and secondary (V2) visual cortices as early as gestational week 20. This sharp binary transition in V1–V2 neuronal subtypes challenges the notion that mid-gestation cortical arealization involves only gradient-like transitions 6,10 . Furthermore, integrating single-nucleus RNA sequencing with MERFISH revealed an early upregulation of synaptogenesis in V1-specific layer 4 neurons. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This study establishes a spatially resolved single-cell analysis paradigm and paves the way for the construction of a comprehensive developmental atlas of the human brain.

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• Perinatal Elimination of Genetically Aberrant Neurons from Human Cerebral Cortex

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-09 · 1 citations

  preprintOpen access

  Abstract Human neurons are postmitotic and long-lived, requiring precise genomic regulation to maintain function over a lifetime. Normal neuronal function is highly dependent on gene dosage, with copy number variants (CNVs) and heterozygous point mutations associated with a host of neurodevelopmental and neuropsychiatric conditions [1–5]. Here, we investigated the landscape of somatic CNVs arising in fetal human brains, and how they change over development, to understand the processes that generate normal neuronal genomes. We sequenced 2,158 single neurons from human postmortem brain using two distinct single cell whole genome sequencing (scWGS) approaches. Tn5-transposase based (TbA) scWGS of 1,327 neurons from 16 individuals ranging in age from gestational week 14 to 90 years old resulted in 8,765 CNVs. Primary template amplification (PTA) was used to assess for CNV from 831 neurons from 12 individuals. Up to 46% of neurons in prenatal cortex showed aberrant genomes, characterized by widespread CNVs of multiple chromosomes, but this proportion reduces by 4-5 fold after birth across the two scWGS approaches (p=7.5×10 −6 , Fisher meta-analysis). We identified micronuclei in the developing cortex in situ , reflecting chromosomal material missegregated during neurodevelopment [6–8]. Neurons with widespread CNVs were eliminated in the perinatal period, while neurons with smaller CNV burden slowly declined during postnatal aging. CNVs in surviving neurons were depleted for genes that are dosage-sensitive or involved in neurodevelopmental disorders (p < 0.05), suggesting selective elimination of neurons with CNVs involving these critical genes. We surveyed 44,861 nuclei with 10X Genomics scATAC/RNAseq and determined that neurons with high CNV burdens also showed abnormal expression of synaptic gene sets, suggesting that abnormal synaptic gene regulation contributes to neuronal elimination. Elimination of defective neuronal genomes during synaptogenesis may represent a critical process of genome quality control and a vulnerable target of factors that contribute to neurodevelopmental disease.

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Frequent coauthors

• Christopher A. Walsh

  Mount Sinai Hospital

  75 shared

• Guo‐li Ming

  69 shared

• Ellen M. DeGennaro

  Boston Children's Hospital

  52 shared

• Taehwan Shin

  Howard Hughes Medical Institute

  48 shared

• Dilenny M. Gonzalez

  Howard Hughes Medical Institute

  48 shared

• Janet Song

  University of California, Los Angeles

  48 shared

• Fadi Jacob

  Emory University

  45 shared

• Hongjun Song

  44 shared

Education

• Ph.D., Biomedical Engineering

  Johns Hopkins University

  2020