About

David B. Frank, MD, PhD, is an Assistant Professor of Pediatrics (Cardiology) at the University of Pennsylvania School of Medicine. He is an attending physician in the Division of Cardiology at the Children's Hospital of Philadelphia and serves as the Assistant Program Director for the Pediatric Cardiology T32 Training Grant at the same hospital. Dr. Frank is a member of the Lung Biology Institute and holds primary faculty positions within the Cardiovascular Institute at the University of Pennsylvania School of Medicine. His research focuses on pulmonary vascular disease, lung development, and pediatric cardiology, contributing to the understanding of pulmonary vein stenosis, pulmonary hypertension, and related vascular conditions in children.

Research topics

• Cell biology
• Biology
• Genetics
• Computational biology

Selected publications

• Integrative vasculogenesis unifies distinct endothelial sources in the developing lung

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-12

  article

  How endothelial cells from distinct developmental sources are integrated into a single continuous vascular system remains unresolved. Here, using the developing mouse lung, we identify a mesenchymal progenitor population that generates endothelial cells de novo and incorporates them into the expanding vasculature through a mechanism we term integrative vasculogenesis. Genetic lineage tracing shows that these progenitors contribute directly to the pulmonary endothelium, defining a source distinct from endothelial cells of the major vessels. Live imaging and single-cell tracking reveal that newly specified angioblasts exhibit high motility, dispersing through stochastic migration before integrating into pre-existing vascular networks. Cell ablation demonstrates that pre-existing networks are required to support the migration, proliferation and survival of nascent endothelial cells. Integrative vasculogenesis is thus distinct from classical vasculogenesis and angiogenesis, providing a framework for how endothelial populations of different origins are assembled into a functional circulatory system.

  PublisherDOI

• BRD4 promotes endodermal cell fate during mammalian lung development

  JCI Insight · 2026-02-03

  articleOpen accessSenior author

  Lung development relies on diverse cell intrinsic and extrinsic mechanisms to ensure proper cellular differentiation and compartmentalization. In addition, it requires precise integration of multiple signaling pathways to temporally regulate morphogenesis and appropriate cell specification. To accomplish this, organogenesis relies on epigenetic and transcriptional regulators to promote cell fate and inhibit alternative cell fates. Using genetic mouse and human embryonic stem cell (hESC) differentiation models, tissue explants, and single-cell transcriptomic analysis, we demonstrated that Bromodomain Containing Protein 4 (BRD4) is required for mammalian lung morphogenesis and cell fate. Endodermal deletion of BRD4 impaired epithelial-mesenchymal crosstalk, leading to disrupted proximal-distal patterning and branching morphogenesis. Moreover, temporal deletion of BRD4 revealed developmental stage-specific defects in airway and alveolar epithelial cell specification with a predominant role in proximal airway cell fate. Similarly, BRD4 promoted lung endodermal cell differentiation into airway lineages in a hESC-derived lung organoid model. Together, these data demonstrate that BRD4 orchestrates early lung morphogenesis and separately regulates cell specification, indicating a multifunctional and evolutionarily conserved role for BRD4 in mammalian lung development.

  PublisherDOI

• Bronchopulmonary dysplasia with pulmonary hypertension associates with semaphorin signaling loss and functionally decreased FOXF1 expression

  Nature Communications · 2025-05-29 · 18 citations

  articleOpen access

  Lung injury in preterm infants leads to structural and functional respiratory deficits, with a risk for bronchopulmonary dysplasia (BPD) that in its most severe form is accompanied by pulmonary hypertension (PH). To identify potential cellular and molecular drivers of BPD in humans, we performed single-cell RNA sequencing of preterm infant lungs with evolving BPD and BPD + PH compared to term infants. Examination of endothelial cells reveals a unique, aberrant capillary cell-state in BPD + PH defined by ANKRD1 expression. Within the alveolar parenchyma in infants with BPD/BPD + PH, predictive signaling analysis identifies surprising deficits in the semaphorin guidance-cue pathway, with decreased expression of pro-angiogenic transcription factor FOXF1. Loss of semaphorin signaling is replicated in a murine BPD model and in humans with causal FOXF1 mutations for alveolar capillary dysplasia (ACDMPV), suggesting a mechanistic link between developmental programs underlying BPD and ACDMPV and uncovering a critical role for semaphorin signaling in normal lung development. How lung epithelial and endothelial cells develop into alveoli is a major knowledge gap, with implications for lung repair in preterm infants. Here, the authors establish a transcriptomic atlas of human neonatal lung disease, identifying semaphorins as pivotal mediators of organogenesis and injury.

  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 access

  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

• Low cardiovascular event rates in patients treated with CAR T-cells: real-world outcomes from two independent cohorts

  European Heart Journal · 2025-11-01

  articleOpen access

  Abstract Background CAR T-cell therapy is becoming a key pillar of medical oncology, used for an expanding range of indications. Its age-independent efficacy makes it a common option for older patients. Considering the increased risk of cardiovascular disease with increasing age, assessing the impact of cardiac comorbidities can help minimizing complications through and enhance treatment outcomes. Objectives This retrospective study evaluates cardiovascular outcomes in patients undergoing CD19- or BCMA-directed CAR T-cell therapy from two large independent databases. Methods Using ICD and procedural codes, the population-based DESTATIS-database (Germany) and the TriNetX Health network (US) were queried for cardiovascular outcomes after CAR T-cell therapy. Results Among 2,545 CAR T-cell cases from Germany and 1,335 patients from the US, we identified short-term severe cardiac events in 51 (2%) and 20 (1.5%) cases with early death documented in 135 (5%) and 16 (1.2%) patients. Patients with preexisting cardiac conditions did not show an increased risk for immune-related complications like cytokine release (OR 1.19, 95%CI 0.77-1.82) or neurotoxicity syndrome (OR 1.59, 95%CI 0.94-2.69). However, they faced higher long-term risks for major cardiovascular events (OR 1.89, 95%CI 1.23-2.91) and kidney failure (OR 2.98, 95%CI 1.85-4.81). Conclusion Cardiovascular complications in CAR T-cell therapy were rare and primarily affected patients with preexisting cardiac conditions. Serious cardiac events were uncommon acutely but increased over time, particularly in cardiology patients. Due to its retrospective nature, the analysis cannot guide patient selection but underscores the need for risk-adapted follow-up and regular cardiological assessments to improve outcomes in patients with cardiac comorbidities.

  PublisherOA PDFDOI

• Inducibility of sustained ventricular tachycardia under conscious sedation

  EP Europace · 2025-05-01

  articleOpen access

  Abstract Background Anesthetic management during ventricular tachycardia (VT) catheter ablation (CA) varies from minimal sedation to general anesthesia (GA). Data on VT inducibility of the patients who underwent CA under conscious sedation (CS) are limited. Methods Data of all patients, who underwent CA of VT at our hospital between 01/ 2022 and 10/2024 were prospectively included. All patients undergone CA under CS with propofol and fentanyl or midazolam when needed. VT induction protocol was performed in all procedures. Two groups were defined: inducibility vs non-inducibility of sustained VT. Localisation of low voltage areas was obtained in offline analysis, according to the 17-segment model. Correlation of VT morphology, pre-und periprocedural parameters as well as endocardial low voltage areas with VT inducibility was assessed. Results A total of 116 procedures in 95 patients (1.2 procedures per patient), mean age 64 (53.75-72) years, 95 (82%) male, 55 (47%) ischemic cardiomyopathy [ICM]). Fentanyl was used in 114 (98%), midazolam in 11 (9%) of procedures. Sustained VT could be induced in 86 (74.1%) patients. Univariate analysis showed, LV ejection fraction ≤ 30% (p=0.004) and NTproBNP level >125 ng/ml (p=0.041) were associated with inducibility of sustained VT. No difference was showing regarding the underlying disease (ICM or non ICM). The individual segments of low voltage did not differ in patients with or without VT induction, with the exception of segment 16. In procedures with inducibility of sustained VT, significant more low voltage was identified in this segment. Overall low voltage substrate was observed more frequently in septal segments in patients with inducible VT than in those without (Figure 1). Conclusion In most patients sustained VT could be induced under CS independent of the underlying disease. Lower LVEF, higher NT-proBNP level and low voltage in apical lateral segment were associated with VT induction.

  PublisherOA PDFDOI

• Longitudinal single-cell profiles of lung regeneration after viral infection reveal persistent injury-associated cell states

  Cell stem cell · 2025-01-15 · 31 citations

  articleOpen access
  PublisherOA PDFDOI

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

  Cell Reports · 2025-04-01 · 2 citations

  articleOpen accessSenior author

  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

• Epithelial outgrowth through mesenchymal rings drives lung alveologenesis

  JCI Insight · 2025-01-07 · 8 citations

  articleOpen access

  Determining how alveoli are formed and maintained is critical to understanding lung organogenesis and regeneration after injury. To study the cellular dynamics of this critical stage of lung development, we have used scanned oblique-plane illumination microscopy of living lung slices to observe alveologenesis in real time at high resolution over several days. Contrary to the prevailing notion that alveologenesis occurs by airspace subdivision via ingrowing septa, we found that alveoli form by ballooning epithelial outgrowth supported by contracting mesenchymal ring structures. Systematic analysis has produced a computational model of finely timed cellular structural changes that drive normal alveologenesis. With this model, we can now quantify how perturbing known regulatory intercellular signaling pathways and cell migration processes affects alveologenesis. In the future, this paradigm and platform can be leveraged for mechanistic studies and screening for therapies to promote lung regeneration.

  PublisherOA PDFDOI

• Pulmonary vasodilator use in very preterm infants in United States children’s hospitals

  Journal of Perinatology · 2025-05-02 · 1 citations

  articleOpen access

  OBJECTIVES: To describe common pulmonary vasodilators (PV), exposure timing, and characteristics associated with their use in very preterm (VP) infants. STUDY DESIGN: Observational study of VP infants discharged from U.S. children's hospitals (2011-2021). PV exposures during hospitalization were identified, and multivariable modeling determined characteristics associated with exposure. RESULTS: Among 37,428 infants, 6.3% received PV. Early inhaled nitric oxide (iNO) and late sildenafil were most common. Early exposure was associated with lower gestational age, aOR: 9.2 (7.3-11.7), 22-25 vs. 29-31 weeks) and small for gestational age (SGA), 2.3 (2.0-2.7). Late exposure was associated with bronchopulmonary dysplasia (BPD) grade, 26.2 (16.8-40.9), grade 3 vs. no BPD) and early PV exposure, 3.7 (2.9-4.8). CONCLUSIONS: Early iNO and late sildenafil are used in VP infants despite limited evidence. Prospective early studies enrolling extremely preterm and SGA infants and late studies enrolling infants with early PV exposure and high-grade BPD would target current evidence gaps.

  PublisherOA PDFDOI

Recent grants

• Wnt-mediated epithelial-endothelial crosstalk in the generation and regeneration of the lung alveolus

  NIH · $797k · 2018–2023

Frequent coauthors

• Edward E. Morrisey

  University of Pennsylvania

  60 shared

• Michael P. Morley

  University of Pennsylvania

  51 shared

• Jarod A. Zepp

  49 shared

• Aravind Sivakumar

  Cornell University

  34 shared

• Prashant Chandrasekaran

  Children's Hospital of Philadelphia

  32 shared

• MinQi Lu

  Children's Hospital of Philadelphia

  31 shared

• Su Zhou

  University of Pennsylvania

  30 shared

• William J. Zacharias

  University of Cincinnati Medical Center

  28 shared

Labs

• David B. Frank LabPI

Education

• Fellow Physician, Pediatric Cardiology

  Children's Hospital of Philadelphia

  2015

• Resident Physician, Pediatrics

  Children's Hospital of Philadelphia

  2011

• PhD, Cell and Developmental Biology

  Vanderbilt University School of Medicine

  2009

• MD

  Vanderbilt University School of Medicine

  2009

• Bachelor of Science, Biochemistry

  University of Nebraska-Lincoln

  1997