About

Jarod A. Zepp, PhD, is an Assistant Professor of Pediatrics in the Department of Pediatrics (Pulmonary Medicine) at the Perelman School of Medicine at the University of Pennsylvania. His educational background includes a B.S. in Biology from the University of Colorado Denver and a Ph.D. in Molecular Medicine from Case Western Reserve University. His research focuses on the development and regeneration of the respiratory system, with particular emphasis on lung alveolus emergence, pulmonary endothelial cell heterogeneity, and epithelial cell fate and patterning. Dr. Zepp has contributed to understanding cellular crosstalk in lung development and regeneration, and his work involves genomic, epigenomic, and biophysical cues that control lung tissue formation. His research aims to elucidate mechanisms underlying lung development, injury response, and regeneration, advancing knowledge in pulmonary biology and potential therapeutic strategies.

Research topics

• Biology
• Cell biology
• Immunology
• Cancer research
• Chemistry

Selected publications

• Airway injury induces alveolar epithelial responses mediated by macrophages

  Cell Reports · 2026-01-23 · 2 citations

  articleOpen access

  Airway injury activates local progenitors and stimulates cell-cell interactions to restore homeostasis, but it is unknown how distal niches are impacted. We utilized mouse models of airway-specific epithelial injury to examine secondary tissue-wide alveolar and immune responses. Single-cell transcriptomics and in vivo validation of mouse models of airway-specific epithelial injury revealed transient, tissue-wide proliferation of alveolar type 2 (AT2) progenitor cells after club cell-specific injury or ablation. Myeloid cells exhibited altered gene expression after club cell loss and were detectable in the bronchoalveolar lavage fluid. The AT2 cell proliferative response was reliant on alveolar macrophages (AMs) exhibiting an injury-induced gene expression program. Overall, these results demonstrate that acute airway damage can trigger myeloid-mediated lung alveolar responses that may contribute to disease susceptibility or dysfunction.

  PublisherDOI

• Dysplastic Epithelial Repair Propagates Chronic Pathology Through the Paracrine Transformation of Pulmonary Fibroblasts

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-05

  articleOpen access

  Abstract Severe lung injury promotes the ectopic accumulation of basal cells in the alveoli and the presence of these dysplastic epithelial cells are strongly associated with regions of pulmonary fibrosis (PF) in diseased lungs. Recent studies have identified a unique subset of “inflammatory” fibroblasts expressing pro-inflammatory genes, especially cytokines involved in monocyte recruitment, that are also enriched in disease and thought to contribute to the onset and progression of PF. Here we show that these two injury-induced cell types are intricately connected, in that dysplastic basal cells generate diffusible signals to robustly induce the inflammatory phenotype in pulmonary fibroblasts. Capitalizing on transcriptomic analysis, we identify the enriched inflammatory signaling pathways in treated fibroblasts and specifically demonstrate that IL-1α secreted by dysplastic basal cells is responsible for this fibroblastic transformation. IL-1α neutralization in vivo is sufficient to significantly reduce the inflammatory fibroblast burden in regions of alveolar bronchiolization, and the resolution of inflammatory fibroblasts in turn reduces CCR2+ immune cell recruitment to these areas. These results suggest dysplastic basal cells play an indirect role in chronic inflammation and fibrotic remodeling through the induction of a proinflammatory fibroblast phenotype and subsequent recruitment of immune cells, establishing a chronic wound healing microenvironment that prolongs localized pathologic remodeling.

  PublisherOA PDFDOI

• Stc1-expressing myofibroblasts are a developmentally distinct lineage cleared through apoptosis in the neonatal lung

  Cell Reports · 2025-12-21

  articleOpen accessSenior author

  mouse line that labels the developmentally transient secondary crest myofibroblasts (SCMFs), distinguishing them from alveolar duct myofibroblasts (DMFs) and smooth muscle. SCMFs expand through clonal proliferation of Stc1-expressing progenitors and are cleared by apoptosis. Deleting the apoptosis effectors Bax and Bak1 in the Stc1 lineage prevented SCMF clearance during alveologenesis. Single-cell RNA sequencing showed that surviving Stc1-lineage cells lose myofibroblast identity while co-expressing SCMF and DMF markers. Embryonic lineage tracing identified distinct progenitors for SCMFs and DMFs, and genetic activation of Hedgehog (Hh) or Wnt signaling pathways failed to interconvert these lineages. These findings establish Stc1-lineage SCMFs as a discrete, developmentally divergent population and define their life cycle independent of other myofibroblast lineages.

  PublisherDOI

• Dynamics of primary cilia in endothelial and mesenchymal cells throughout mouse lung development

  Developmental Dynamics · 2025-03-08 · 5 citations

  articleOpen access

  Cilia are specialized structures found on a variety of mammalian cells, with variable roles in the transduction of mechanical and biological signals (by primary cilia, PC), as well as in the generation of fluid flow (by motile cilia). Their critical role in the establishment of a left-right axis in early development is well described, as well as in the defense immune function of multiciliated upper airway epithelium. By contrast, detailed analysis of the ciliary status of specific cell types during organogenesis and postnatal development has received less attention. In this study, we investigate the progression of ciliary status within the endothelium and mesenchyme of the lung. Remarkably, we find that pulmonary endothelial cells (ECs) lack PC at all stages of development, except in low numbers in the proximal portions of older pulmonary arteries. Mesenchymal cells, by contrast, widely exhibit PC in early development, and a large subset of PDGFRα+ fibroblasts maintain PC into adulthood. The dynamic and differential ciliation of multiple cellular populations in the developing lung both challenges prior assertions that PC are found on all cells and highlights a need to understand their spatiotemporal functions.

  PublisherOA PDFDOI

• Stc1-expressing myofibroblasts are a developmentally distinct lineage cleared through intrinsic apoptosis in the neonatal lung

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-15

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Lung myofibroblasts are necessary for early postnatal alveolar growth and develop again during pathological fibrosis. Determining the unique contributions of multiple myofibroblast lineages to development and disease is hampered by a lack of genetic tools to distinguish between them. In this study, we generated a Stc1 CreERT2 mouse line that faithfully labels the developmentally transient secondary crest myofibroblasts (SCMF) and distinguishes SCMFs from alveolar duct myofibroblasts (DMF) and smooth muscle. SCMF populations expand by clonal proliferation of Stc1 -expressing progenitors and contract by apoptosis. We deleted the intrinsic apoptosis effectors Bax and Bak1 in the Stc1-lineage, which prevented SCMF clearance during alveologenesis. Single-cell RNA-seq revealed that residual Stc1-lineage cells lacking Bax and Bak1 lose myofibroblast identity but express a combination of SCMF and DMF marker genes. Embryonic lineage tracing identified that SCMFs and DMFs have distinct progenitor populations with unique niches, and genetic activation of developmentally important signaling pathways could not interconvert these lineages. These findings establish Stc1-lineage SCMFs as a discrete population, developmentally divergent from DMFs, and define their life cycle in isolation from other myofibroblast lineages.

  PublisherOA PDFDOI

• Age-dependent immune responses and resident cell dynamics in young mice following pneumonia

  iScience · 2025-11-26

  articleOpen access

  on the lung. This study highlighted how early-life immune ontogeny impacts disease susceptibility, opening avenues for future research to identify therapeutic targets to enhance resistance to respiratory infections for the most vulnerable populations.

  PublisherDOI

• Emergence of inflammatory fibroblasts with aging in Hermansky-Pudlak syndrome associated pulmonary fibrosis

  Communications Biology · 2025-02-22 · 10 citations

  articleOpen access

  The longitudinal cellular interactions that drive pulmonary fibrosis are not well understood. To investigate the disease underpinnings associated with fibrosis onset and progression, we generated a scRNA-seq atlas of lungs from young and aged mouse models of multiple subtypes of Hermansky-Pudlak syndrome (HPS), a collection of rare autosomal recessive diseases associated with albinism, platelet dysfunction, and pulmonary fibrosis. We have identified an age-dependent increase in SAA3+ inflammatory lung fibroblasts in HPS mice, including in double-mutant HPS1-2 mice which develop spontaneous fibrosis. HPS1 fibroblasts show increased expression of IL-1R1, whereas alveolar type II epithelial cells from HPS2 mice induce the inflammatory gene signature in co-cultured fibroblasts. scRNA-seq of lung tissue from three HPS1 patients similarly shows the presence of inflammatory fibroblasts and increased IL1R1 expression on fibroblasts. These data posit complex interactions between dysfunctional epithelial cells, inflammatory fibroblasts, and recruited immune cells, suggesting potential opportunities for mitigation of the fibrotic cascade. Single cell RNA sequencing atlases of HermanskyPudlak syndrome elucidate cellular abnormalities including emergence of inflammatory fibroblasts that are associated with pulmonary fibrosis.

  PublisherOA PDFDOI

• A spatiotemporal cell atlas of cardiopulmonary progenitor cell allocation during development

  Cell Reports · 2025-04-01 · 2 citations

  articleOpen access

  CPPs at E8.5 and performed single-cell RNA sequencing on collected progeny across the developmental lifespan. Using computational analyses, we created a CPP-derived cell atlas that revealed a previously underappreciated spectrum of CPP-derived cell lineages, including all lung mesodermal lineages, ventricular cardiomyocytes, and epicardial and pericardial cells. By integrating spatial mapping with computational cell trajectory analysis and transcriptional profiling, we have provided a potential molecular and cellular roadmap for cardiopulmonary development.

  PublisherDOI

• Marginated Neutrophils in the Lungs Effectively Compete for Nanoparticles Targeted to the Endothelium, Serving as a Part of the Reticuloendothelial System

  ACS Nano · 2024-08-06 · 24 citations

  articleOpen access

  Nanomedicine has long pursued the goal of targeted delivery to specific organs and cell types but has yet to achieve this goal with the vast majority of targets. One rare example of success in this pursuit has been the 25+ years of studies targeting the lung endothelium using nanoparticles conjugated to antibodies against endothelial surface molecules. However, here we show that such "endothelial-targeted" nanocarriers also effectively target the lungs' numerous marginated neutrophils, which reside in the pulmonary capillaries and patrol for pathogens. We show that marginated neutrophils' uptake of many of these "endothelial-targeted" nanocarriers is on par with endothelial uptake. This generalizes across diverse nanomaterials and targeting moieties and was even found with physicochemical lung tropism (i.e., without targeting moieties). Further, we observed this in ex vivo human lungs and in vivo healthy mice, with an increase in marginated neutrophil uptake of nanoparticles caused by local or distant inflammation. These findings have implications for nanomedicine development for lung diseases. These data also suggest that marginated neutrophils, especially in the lungs, should be considered a major part of the reticuloendothelial system (RES), with a special role in clearing nanoparticles that adhere to the lumenal surfaces of blood vessels.

  PublisherOA PDFDOI

• Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome

  JCI Insight · 2024-12-19 · 8 citations

  articleOpen access

  Hermansky-Pudlak syndrome (HPS) is a genetic disorder of endosomal protein trafficking associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single-mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double-mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. We utilized HPS mouse models and human lung tissue to investigate mechanisms of AT2 cell dysfunction driving fibrotic remodeling in HPS. Starting at 8 weeks of age, HPS mice exhibited progressive loss of AT2 cell numbers. HPS AT2 cell function was impaired ex vivo and in vivo. Incorporating AT2 cell lineage tracing in HPS mice, we observed aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and p53 activation. Lineage-tracing and organoid-modeling studies demonstrated that HPS AT2 cells were primed to persist in a Keratin-8-positive reprogrammed transitional state, mediated by p53 activity. Intrinsic AT2 progenitor cell dysfunction and p53 pathway dysregulation are mechanisms of disease in HPS-related pulmonary fibrosis, with the potential for early targeted intervention before the onset of fibrotic lung disease.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K99HL141684

  NIH · $281k · 2020

• Defining the molecular determinants of mesenchymal lineage allocation in lung development and disease

  NIH · $747k · 2020–2024

Frequent coauthors

• Xiaoxia Li

  Southern Medical University

  67 shared

• Ling Wu

  67 shared

• Junjie Zhao

  Fuyang Maternity and Child Health Care Hospital

  53 shared

• David B. Frank

  49 shared

• Bradley N. Martin

  Brigham and Women's Hospital

  41 shared

• Edward E. Morrisey

  University of Pennsylvania

  40 shared

• Michael P. Morley

  University of Pennsylvania

  36 shared

• Bing Su

  Agency for Science, Technology and Research

  27 shared

Labs

• Jarod A. Zepp LaboratoryPI