About

Amy Wagers is the Forst Family Professor of Stem Cell and Regenerative Biology at Harvard University. Her research explores the mechanisms that regulate the function of blood- and muscle-forming and forming stem cells, with the goal of optimizing their potential for treating diseases such as cancer, anemia, muscular dystrophy, and diabetes. Her work focuses on understanding how regenerative processes maintain proper cell numbers and repair damaged tissues, emphasizing the role of stem and progenitor cells in tissue homeostasis and regeneration. Her research has practical implications for therapeutic strategies, including transplantation and endogenous manipulation to enhance tissue repair.

Research topics

• Biology
• Genetics
• Cell biology
• Immunology
• Computational biology
• Anatomy
• Bioinformatics
• Literature
• Environmental ethics
• Philosophy
• Art

Selected publications

• Modulation of Nudt21 levels reveals dose-dependent roles of alternative polyadenylation in tissue regeneration

  Nature Communications · 2026-01-24

  articleOpen access

  Stem cells continually self-renew and differentiate to sustain tissue homeostasis, yet the role of post-transcriptional mechanisms in guiding these processes remains incompletely understood. Here, we demonstrate that the regulation of 3'UTR length via alternative mRNA polyadenylation (APA) is essential for stem cell function across diverse tissues. Modulating the APA regulator Nudt21 reveals that stem cell self-renewal and differentiation depend on distinct dosage thresholds and thus can be uncoupled. Specifically, moderate Nudt21 suppression elicits a maturation arrest of stem cells due to 3'UTR-shortening of differentiation-associated mRNAs that escape miRNA regulation and perturb ceRNA networks. By contrast, complete Nudt21 suppression additionally shortens the 3'UTRs of mRNAs encoding essential multiprotein complexes, including the nuclear pore, leading to complex destabilization, proteotoxic stress, DNA damage, and cell cycle arrest. Critically, deletion of the alternative 3'UTRs of individual nucleoporins recapitulates defects observed with Nudt21 loss. We further demonstrate that the co-translational assembly of dozens of protein complexes is impaired in Nudt21-deficient cells, providing a mechanistic framework for compromised complex integrity. Collectively, our results show that APA plays distinct, dose-dependent roles in stem cell homeostasis by fine-tuning the expression of differentiation-associated genes and coordinating the biogenesis of multiprotein complexes essential for cell cycle progression.

  PublisherDOI

• Smart Lids for deep multi-animal phenotyping in standard home cages

  Frontiers in Behavioral Neuroscience · 2026-01-20 · 1 citations

  articleOpen access

  The reproducibility crisis and translational gap in preclinical research underscore the need for more accurate and reliable methods of health monitoring in animal models. Manual testing is labor-intensive, low-throughput, prone to human bias, and often stressful for animals. Although many smart cages have been introduced, they have seen limited adoption due to either low throughput (being limited to single animals), low data density (a few metrics only), high costs, a need for new space or infrastructure in the vivarium, high complexity use, or a combination of the above. Although technologies for video-based single-animal tracking have matured, no existing technology enables robust and accurate multi-animal tracking in standard home cages. To solve these problems, we built a new type of assay device: the Smart Lid. Smart Lids mount to existing racks, above standard home cages and stream video and audio data, turning regular racks into high-throughput monitoring platforms. To solve the multi-animal tracking problem, we developed a new computer vision pipeline (MOT - Multi-Organism Tracker) along with a new ear tag purpose-designed for computer vision tracking. MOT achieves over 97% accuracy in multi-animal tracking while maintaining an affordable runtime cost (less than $100 per month). The pipeline returns 21 health-related metrics, covering activity, feeding, drinking, rearing, climbing, fighting, cage positioning, social interactions and sleeping, with additional metrics under development.

  PublisherOA PDFDOI

• <i>In vivo</i> base editing via single myotrophic adeno-associated viruses in dystrophic mouse muscle and satellite cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-10

  articleOpen accessSenior authorCorresponding

  Abstract Duchenne muscular dystrophy (DMD) is the most common, lethal X-linked neuromuscular disorder of childhood and is caused by mutations in the Dmd gene that disrupt dystrophin expression. Although adeno-associated virus-mediated gene therapies hold tremendous promise for DMD treatment, their clinical applications have been limited by dose-dependent vector and genome-level toxicities. Here, we developed and tested a single-vector adenine base editing strategy as a potentially safer genome editing approach to recode the pathogenic nonsense mutation into a benign missense mutation in mdx 4cv DMD mouse model. Delivered using a muscle-tropic adeno-associated virus (MyoAAV) at a clinically-feasible dose (4E13 VG/kg), this strategy enabled detectable molecular recoding of the mdx 4cv mutation in mice ranging in age from 3 days to 6 months. Yet, the overall efficiency and therapeutic impact of in vivo base editing with this system was highest in mice treated at the juvenile stage, with animals administered MyoAAV vectors at 3 weeks of age showing robust recovery of dystrophin expression and significant improvement in muscle contractile properties only one month later. Notably, introduction of adenine base editors either earlier in development, in neonatal mice, or later, in adulthood, yielded substantially lower editing efficiencies, particularly in muscle satellite cells whose editing is essential to ensure durable rescue of dystrophin expression in growing and regenerating muscle. Taken together, these results demonstrate the therapeutic potential of single-vector adenine base editing for DMD and underscore the importance of recipient age and disease stage in achieving optimal treatment outcomes for this and other genetic muscle disorders.

  PublisherDOI

• Activated GDF11/8 subforms predict cardiovascular events and mortality in humans

  Nature Communications · 2025-07-15 · 1 citations

  articleOpen access

  Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline. The predictive value of blood levels of GDF11/8 proteins in humans for future disease outcomes has been unclear. Here, the authors show that low levels of specific activated GDF11/8 subforms are strongly associated with future cardiovascular events, mortality, and dementia risk.

  PublisherOA PDFDOI

• Multi-scale footprinting

  Zenodo (CERN European Organization for Nuclear Research) · 2025-02-13 · 1 citations

  datasetOpen access

  Data associated with the multi-scale footprinting project. (1) Tn5_NN_model.h5 Pre-trained CNN-based Tn5 bias model implemented with Keras. Takes local DNA sequence context as input and predicts Tn5 insertion bias. See tutorial for how to use this model. (2) Tn5ModelTutorial.ipynb Tutorial showing how to use the pre-trained Tn5 bias model to score input sequences. (3) hg38Tn5Bias.tar.gz, hg19Tn5Bias.tar.gz, mm10Tn5Bias.tar.gz, mm39_bias_v2.h5, panTro6Tn5Bias.tar.gz, sacCer3Tn5Bias.tar.gz, dm6Tn5Bias.tar.gz, danRer11Tn5Bias.tar.gz, ce11Tn5Bias.tar.gz h5 files containing the genome-wide Tn5 bias pre-computed using our convolutional neural net model. (4) dispModel.tar.gz Zipped folder containing Tn5 cutting dispersion models for each footprint window radius. The footprint window size in our paper refers to the diameter the footprint window, which is twice the number listed here. During footprinting, these models are loaded into the footprintingProject object and then used for footprinting. (5) cisBP_mouse_pwms_2021.rds, cisBP_human_pwms_2021.rds Motif PWMs used in our study. (6) TFBS_model.h5 Pre-trained footprint-to-TF binding prediction models. The models takes local multi-scale footprints as input and predict whether a genomic position is bound by a TF if the corresponding motif is present. This is obsolete. For the best performance of TF binding prediction, please use our seq2PRINT-based TF binding prediction. (7) clusterLabels.txt, clusterLabelsAllTFs.txt Cluster labels of TFs. clusterLabels.txt is the clustering result directly obtained from clustering multi-scale footprints of all TFs with ChIP data. clusterLabelsAllTFs.txt includes other TFs without ChIP data. The cluster membership of these TFs were assigned based on motif homology among TFs. (8) BMMCTutorial.tar.gz Data needed for our R version tutorial. Content of this foder can be put into the /data/BMMCTutorial folder. (9) PBMC_bulk_ATAC_tutorial fragments files Files used by our PBMC bulk ATAC tutorial for scPrinter. See https://github.com/buenrostrolab/scPrinter for details. (10) PBMC_bulk_ATAC_tutorial example result TFBS bigwigs (Bcell_0_TFBS.bigwig, Bcell_1_TFBS.bigwig, Monocyte_0_TFBS.bigwig, Monocyte_1_TFBS.bigwig , Tcell_0_TFBS.bigwig, Tcell_1_TFBS.bigwig). Example result files generated by our PBMC bulk ATAC tutorial for scPrinter. See https://github.com/buenrostrolab/scPrinter for details. Here we filtered ATAC-seq peaks based on accessibility, keeping ~70k highly accessible peaks. (11) CTCF_degron.tar.gz Input data used for the CTCF degron analysis. See https://github.com/buenrostrolab/PRINT/blob/main/analyses/degron/ENCODE_CTCF_degron.ipynb for details. (12) obsBias.tsv Input data used for training the Tn5 bias model. For more details see https://github.com/buenrostrolab/PRINT/blob/main/code/predictBias.py (line 84)

  PublisherDOI

• Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks

  The Journal of Experimental Medicine · 2025-01-28 · 9 citations

  articleOpen access

  Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.

  PublisherOA PDFDOI

• In situ gene editing of hematopoietic stem cells via AAV-delivered CRISPR guide RNAs

  Blood Advances · 2025-09-24 · 1 citations

  articleOpen accessSenior author

  ABSTRACT: Hematopoietic stem cells (HSCs) are self-renewing, multipotent, and engraftable precursors of all blood cells. Efficient delivery of therapeutic gene products and gene editing machinery to correct disease-causing gene variants in endogenous HSCs while they remain in the body holds exciting potential to leverage HSC potency for the treatment of monogenic blood disorders. Toward this goal, we used adeno-associated virus (AAV) to deliver CRISPR guide RNAs (gRNAs) to edit HSC genomes in situ in Ai9;SpCas9-EGFP transgenic mice carrying a Cas9-activatable Lox-STOP-Lox-tdTomato reporter cassette together with a constitutive SpCas9-2A-EGFP. Using a variety of conditions and vector designs, we tested whether systemic administration to these mice of AAVs carrying SpCas9-compatible gRNAs designed to cut DNA upstream and downstream of the STOP cassette would induce tdTomato expression in HSCs. Our findings identify self-complementary AAVs (scAAVs) and increased ratio of guide to Cas9 as parameters facilitating higher editing efficiency. Of note, we find preserved multilineage output and engraftability of HSCs upon scAAV-gRNA editing. In an example application of this technology, we explore the potential for in situ HSC gene editing by dual AAV-CRISPR delivery and demonstrate robust gene modification, concurrent with induction of therapeutic fetal hemoglobin, in a sickle cell disease mouse model modified to express SpCas9. In summary, this work offers a sensitive and adaptable platform that allows robust modification of HSC genomes in situ.

  PublisherOA PDFDOI

• Multiscale footprints reveal the organization of cis-regulatory elements

  Nature · 2025-01-22 · 45 citations

  articleOpen access

  . However, methods for measuring the organization of effector proteins at CREs across the genome are limited, hampering efforts to connect CRE structure to their function in cell fate and disease. Here we developed PRINT, a computational method that identifies footprints of DNA-protein interactions from bulk and single-cell chromatin accessibility data across multiple scales of protein size. Using these multiscale footprints, we created the seq2PRINT framework, which uses deep learning to allow precise inference of transcription factor and nucleosome binding and interprets regulatory logic at CREs. Applying seq2PRINT to single-cell chromatin accessibility data from human bone marrow, we observe sequential establishment and widening of CREs centred on pioneer factors across haematopoiesis. We further discover age-associated alterations in the structure of CREs in murine haematopoietic stem cells, including widespread reduction of nucleosome footprints and gain of de novo identified Ets composite motifs. Collectively, we establish a method for obtaining rich insights into DNA-binding protein dynamics from chromatin accessibility data, and reveal the architecture of regulatory elements across differentiation and ageing.

  PublisherOA PDFDOI

• Recombinant GDF11 Promotes Recovery in a Rat Permanent Ischemia Model of Subacute Stroke

  Stroke · 2025-02-06 · 2 citations

  articleOpen access

  BACKGROUND: Stroke remains a leading cause of death and disability, underscoring the urgent need for treatments that enhance recovery. GDF11 (growth differentiation factor 11), a member of the TGF-β (transforming growth factor-β) superfamily, is a circulating protein involved in cellular development and tissue repair. GDF11 has gained attention for its potential regenerative properties in aging and disease contexts, making it a candidate for stroke recovery therapies. METHODS: The therapeutic benefits of rGDF11 (recombinant GDF11) were evaluated using a rat ischemic stroke model, in which focal cerebral infarcts were induced in 8- to 10-week-old young adult male Sprague-Dawley rats by permanently occluding the proximal right middle cerebral artery. Rats received single or multiple doses of rGDF11 (0.1-4 mg/kg) or vehicle from 24 to 72 hours post-injury. Sensorimotor functions were evaluated, and brain and serum samples were examined to determine the mechanisms of action and identify biomarkers, using immunofluorescence, target-specific ELISAs, and an aptamer-based proteomics platform. RESULTS: We confirmed rGDF11 activity in vitro and in established in vivo mouse models of cardiac hypertrophy and glucose metabolism and assessed the efficacy of rGDF11 treatment in 6 preclinical stroke studies using independent Contract Research Organizations, with all study animals and treatment groups blinded. All 6 studies revealed consistent improvement in sensorimotor outcomes with rGDF11. rGDF11-treated rats showed increased cortical vascularization and radial glia in the ventricular zone. Serum analysis revealed that rGDF11 caused dose-dependent decreases in CRP (C-reactive protein) and identified novel pharmacodynamic biomarkers and pathways associated with potential mechanisms of action of rGDF11. CONCLUSIONS: These results demonstrate that systemically delivered rGDF11 enhances neovascularization, reduces inflammation, promotes neurogenesis, and improves sensorimotor function post-injury in a rat model of ischemic stroke. More importantly, these data define an optimized and clinically feasible rGDF11 dosing regimen for therapeutic development in ischemic stroke and identify a panel of candidate pharmacodynamic and mechanistic biomarkers to support clinical translation.

  PublisherOA PDFDOI

• Langerhans cells renew in the skin throughout life under steady-state conditions

  Universität Zürich, ZORA · 2025-05-01

  articleOpen access

  Langerhans cells (LCs) are bone marrow (BM)-derived epidermal dendritic cells (DCs) that represent a critical immunologic barrier to the external environment, but little is known about their life cycle. Here, we show that in lethally irradiated mice that had received BM transplants, LCs of host origin remained for at least 18 months, whereas DCs in other organs were almost completely replaced by donor cells within 2 months. In parabiotic mice with separate organs, but a shared blood circulation, there was no mixing of LCs. However, in skin exposed to ultraviolet light, LCs rapidly disappeared and were replaced by circulating LC precursors within 2 weeks. The recruitment of new LCs was dependent on their expression of the CCR2 chemokine receptor and on the secretion of CCR2-binding chemokines by inflamed skin. These data indicate that under steady-state conditions, LCs are maintained locally, but inflammatory changes in the skin result in their replacement by blood-borne LC progenitors.

  PublisherDOI

Recent grants

• In vivo gene editing of hematopoietic stem and progenitor cells

  NIH · $1.7M · 2018–2024

• Uncovering molecular effectors of mammalian aging

  NIH · $5.9M · 2018–2025

• NIH Grant R56AG052979

  NIH · $203k · 2017

• Pre Clinical Discovery Core

  NIH · $39.3M · 2008–2027

• Investigating GDF11 and MSTN as candidate circulating geronic factors

  NIH · $2.0M · 2017–2023

Frequent coauthors

• Simone Hettmer

  University of Freiburg

  403 shared

• Richard Lee

  200 shared

• Jennifer L. Shadrach

  Palo Alto University

  181 shared

• Ryan G. Walker

  Harvard Stem Cell Institute

  138 shared

• Lee L. Rubin

  Broad Institute

  119 shared

• Thomas B. Thompson

  University of Cincinnati

  111 shared

• Tata Nageswara Rao

  University of St. Gallen

  107 shared

• Leo D. Wang

  102 shared

Education

• Ph.D., Developmental Biology

  Harvard University

  1998

• B.S., Biology

  University of California, San Diego

  1993