About

Dr. Fei Chen is a Principal Investigator and Core Faculty member at the Broad Institute as well as an assistant professor at Harvard Stem Cell and Regenerative Biology. He earned his Ph.D. in biological engineering from the Massachusetts Institute of Technology in 2016. Following his doctoral studies, Fei Chen was a Schmidt Fellow at the Broad Institute from 2017 to 2020. His professional biography highlights his dual roles in leading research at the Broad Institute and Harvard, reflecting his expertise and leadership in biological engineering and stem cell biology.

Research topics

• Biology
• Genetics
• Computational biology
• Computer Science
• Artificial Intelligence
• Evolutionary biology
• Cell biology
• Chemistry
• Ecology
• Medicine
• Neuroscience
• Materials science
• Endocrinology
• Bioinformatics
• Algorithm
• Database
• Anatomy
• Pathology
• Cancer research
• Internal medicine

Selected publications

• Sample barcoding-associated technical variation in probe-based single-cell RNA sequencing

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-08

  articleOpen accessSenior authorCorresponding

  Abstract Probe-based single cell RNA sequencing approaches are increasingly becoming a technology of choice for profiling gene expression at scale and in archival tissues. The 10x Genomics Flex v1 assay enables cost-effective and high-sensitivity single-cell RNA sequencing by splitting samples across up to 16 uniquely barcoded probe sets before pooling and loading onto a single lane of a microfluidic chip. A natural consequence of this design is to leverage probe set barcoding as a sample barcoding strategy for case-control experiments. However, we observed that Flex v1 probe set barcode identity drives substantial technical variation between probe set barcodes, an effect that is reproducible across lanes and independent datasets. When Flex v1 probe set barcodes are confounded with biological sample identity, a concerning number of differentially expressed genes at standard thresholds are false positives. The Flex v2 assay, which decouples sample barcoding from probe set hybridization, significantly reduces this artifact. As the field continues to expand adoption of probe-based assays, our findings introduce probe set barcoding as an underappreciated source of technical variation in single-cell assays and emphasize the importance of experimental design when using probe-based sequencing technologies.

  PublisherDOI

• Flexible nanoelectronics reveal arrhythmogenesis in transplanted human cardiomyocytes

  Science · 2025-10-16 · 4 citations

  article

  The transplantation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) offers a potential treatment for heart failure, but arrhythmogenic automaticity can arise from these transplanted cells. In this study, we investigated the effects of RADA16, a clinically approved self-assembling peptide that forms nanofibers after injection, on the vascularization, myofibril structure, and electrophysiological adaptation of hiPSC-CMs transplanted into rat hearts. RADA16 accelerated the transition of hiPSC-CMs toward adultlike gene expression profiles, enhanced sarcomere organization, and improved vascularization in the transplanted site. Flexible mesh nanoelectronics revealed fibrillation of transplanted hiPSC-CMs within the beating recipient heart, and RADA16 drastically reduced the automaticity of hiPSC-CMs. Our findings demonstrate the potential of self-assembling nanofibers to advance cardiac cell therapy and how flexible mesh nanoelectronics technology could improve safety.

  PublisherDOI

• Tissue architecture dynamics underlying immune development and decline in the thymus

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-02 · 2 citations

  preprintOpen accessSenior author

  The age-associated decline in adaptive immune function, widely observed in vertebrates, has been attributed to thymic involution. To gain insights into the structural and transcriptional changes underlying this phenomenon, we employed high-resolution spatial transcriptomics and T-cell receptor (TCR) sequencing in mice. By analyzing 21 thymus samples spanning mouse lifespan, we uncovered significant alterations in thymic organization, including disrupted T cell development and the emergence of B cell aggregates. We also observed age- related changes in cell-cell interactions, marked by increased antigen-presenting cell presence in thymic medullary regions and a shift from inflammatory to suppressive macrophages, fostering an immunosuppressive niche. Furthermore, aged thymus tissues exhibited an abundance of regions with reduced TCR diversity, accompanied by distinct changes to gene expression profiles. Our study establishes a valuable reference for understanding aging-related alterations in adaptive immunity, revealing mechanisms underlying age-induced immunological decline.

  PublisherOA PDFDOI

• Transient hepatic reconstitution of trophic factors enhances aged immunity

  Nature · 2025-12-17 · 8 citations

  articleOpen access

  Abstract Ageing erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy and vaccine failure 1–3 . Attempts to rejuvenate immune function have yielded only modest results and are limited by toxicity or lack of clinical feasibility 1,3–5 . Here we show that the liver can be transiently repurposed to restore age-diminished immune cues and improve T cell function in aged mice. These immune cues were found by performing multi-omic mapping across central and peripheral niches in young and aged animals, leading to the identification of Notch and Fms-like tyrosine kinase 3 ligand (FLT3L) pathways, together with interleukin-7 (IL-7) signalling, as declining with age. Delivery of mRNAs encoding Delta-like ligand 1 (DLL1), FLT3L and IL-7 to hepatocytes expanded common lymphoid progenitors, boosted de novo thymopoiesis without affecting haematopoietic stem cell (HSC) composition, and replenished T cells while enhancing dendritic cell abundance and function. Treatment with these mRNAs improved peptide vaccine responses and restored antitumour immunity in aged mice by increasing tumour-specific CD8 + infiltration and clonal diversity and synergizing with immune checkpoint blockade. These effects were reversible after dosing ceased and did not breach self-tolerance, in contrast to the inflammatory and autoimmune liabilities of recombinant cytokine treatments 6,7 . These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.

  PublisherDOI

• Induction of menstruation in mice reveals the regulation of menstrual shedding

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-09 · 5 citations

  preprintOpen access

  During menstruation, an inner layer of the endometrium is selectively shed, while an outer, progenitor-containing layer is preserved to support repeated regeneration. Progress in understanding this compartmentalization has been hindered by the lack of suitable animal models, as mice and rats do not menstruate. Here, we present transgenic mouse models that recapitulate the key anatomical, functional, and transcriptional features of human menstruation through targeted chemogenetic activation of premenstrual differentiation. Using single-cell spatial transcriptomics, we define a new paradigm for spatially regulated fibroblast differentiation that drives pre-menstrual endometrial layering and ultimately determines the extent of tissue shedding. Our results revise a century-old view of endometrial shedding and regeneration and establish new transgenic mice as powerful tools to advance menstruation research.

  PublisherOA PDFDOI

• Subcellular level spatial transcriptomics with PHOTON

  Nature Communications · 2025-05-14 · 4 citations

  articleOpen access

  The subcellular localization of RNA is closely linked to its function. Many RNA species are partitioned into organelles and other subcellular compartments for storage, processing, translation, or degradation. Thus, capturing the subcellular spatial distribution of RNA would directly contribute to the understanding of RNA functions and regulation. Here, we present PHOTON, a method which combines high resolution imaging with high throughput sequencing to achieve spatial transcriptome profiling at subcellular resolution. We demonstrate PHOTON as a versatile tool to accurately capture the transcriptome of target cell types in situ at the tissue level such as granulosa cells in the ovary, as well as RNA content within subcellular compartments such as the nucleoli, the mitochondria, and the stress granules. Using PHOTON, we also reveal the functional role of m6A modifications on mRNA partitioning into stress granules. These results collectively demonstrate that PHOTON is a flexible and generalizable platform for understanding subcellular molecular dynamics through the transcriptomic lens. Rajachandran, Xu, and colleagues present PHOTON, a subcellular resolution spatial transcriptomics technology that allows the capturing of RNA information within various subcellular compartments under the native cellular context.

  PublisherOA PDFDOI

• Expansion in situ genome sequencing links nuclear abnormalities to aberrant chromatin regulation

  Science · 2025-05-29 · 8 citations

  article

  Microscopy and genomics are used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and super-resolution localization of nuclear proteins in single cells. Applying ExIGS to progeria-derived fibroblasts revealed that lamin abnormalities are linked to hotspots of aberrant chromatin regulation that may erode cell identity. Lamin was found to generally repress transcription, suggesting that variation in nuclear morphology may affect gene regulation across tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform with which to link nuclear abnormalities to gene regulation, offering insights into disease mechanisms.

  PublisherDOI

• <scp>TCF21</scp> Downregulation Induces <scp>ERO1A</scp> Expression and Upregulates <scp>IDO1</scp> to Trigger Immune Escape in Lung Adenocarcinoma

  Apmis · 2025-11-01

  articleOpen access1st author

  ABSTRACT Transcription factor TCF21 is downregulated in lung adenocarcinoma (LUAD), contributing to poor treatment outcomes. This study explores its role in regulating CD8 + T cell‐mediated antitumor immunity and metastasis. TCF21 expression was analyzed via TCGA. Downstream target ERO1A was identified using JASPAR prediction, validated by dual‐luciferase/ChIP assays. LUAD mouse models and cell experiments (Transwell, flow cytometry, LDH/ELISA) assessed impacts on metastasis and CD8 + T cell function. The results showed that TCF21 overexpression inhibited LUAD migration/invasion and enhanced CD8 + T cell cytotoxicity. Mechanistically, TCF21 repressed ERO1A transcription, reducing IDO1 expression. Conversely, ERO1A overexpression promoted metastasis and suppressed CD8 + T cell activity via IDO1 upregulation. Knockdown of ERO1A or IDO1 blockade reversed the pro‐tumor effects of TCF21 loss. In conclusion, TCF21 downregulation in LUAD activates the ERO1A‐IDO1 axis, enabling immune escape from CD8 + T cell killing and accelerating malignancy.

  PublisherOA PDFDOI

• Author response: Spatially defined multicellular functional units in colorectal cancer revealed from single cell and spatial transcriptomics

  2025-12-12

  peer-reviewOpen access

  An integrative analysis of scRNA-seq and spatial transcriptomics provides complementary views into the biology of pre-clinical colorectal cancer models in mice with possible applications to the human system.

  PublisherDOI

• Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors

  Nature Communications · 2025-12-20 · 2 citations

  articleOpen access

  A central challenge in cancer research is to identify the secreted factors that sustain tumor cell survival. This is best exemplified in Hodgkin lymphoma, where malignant cells constitute a minor fraction of the tumor and rely on signals from the microenvironment for survival. Using genome-wide transcriptional profiling with spatial and single-cell resolution, we show that the neighborhood around malignant cells forms a distinct niche of 31 non-malignant cell types, enriched in helper T cells and myeloid cells, but depleted of plasma cells. Moreover, our spatial analysis nominates IL13 as a candidate survival factor. Recombinant IL13 augments malignant cell growth in vitro, and genome-wide loss-of-function screens across >1000 human cancer cell lines identify IL4R and IL13RA1, heterodimeric components of the IL13 receptor, as uniquely essential in Hodgkin lymphoma. Importantly, blocking antibodies phenocopy genetic inactivation. Our findings provide a biological rationale for testing IL13-directed therapies, which are already FDA-approved, in Hodgkin lymphoma. Hodgkin Reed Sternberg (HRS) cells and their surrounding microenvironment in Hodgkin lymphoma remain poorly characterized. Here, the authors perform genome-wide transcriptional profiling with spatial and single-cell resolution to explore the cellular and molecular composition of the Hodgkin lymphoma microenvironment and used machine learning to identify IL13 as a potential HRS cell survival factor.

  PublisherDOI

Recent grants

• A platform for scalable spatial single cell genomics

  NIH · $5.3M · 2019–2028

• Characterizing glioma heterogeneity with novel multiplexed nanoscale imaging technologies

  NIH · $2.2M · 2017–2022

• Reduced Reactive Oxygen Species and Oxidative Phosphorylation in Arsenic-Induced Cancer Stem Cells

  NIH · $1.9M · 2021–2023

• Clinical implementations of spatial transcriptomics in tumors

  NIH · $1.4M · 2020–2023

• In situ ATAC-seq, a novel technology for structural epigenomics

  NIH · $708k · 2017–2019

Frequent coauthors

• Edward S. Boyden

  McGovern Institute for Brain Research

  90 shared

• Evan Z. Macosko

  Broad Institute

  83 shared

• Evan Murray

  Broad Institute

  77 shared

• Aviv Regev

  Broad Institute

  66 shared

• Anubhav Sinha

  McGovern Institute for Brain Research

  48 shared

• Asmamaw T. Wassie

  University of Pennsylvania

  40 shared

• Shahar Alon

  Bar-Ilan University

  35 shared

• Jialiang Huang

  East China University of Science and Technology

  34 shared

Labs

• The Chen LabPI