About

Michael F. Beers, MD, is the Robert L. Mayock and David A. Cooper Professor in Pulmonary Medicine at the Perelman School of Medicine, University of Pennsylvania. He serves as a Medical Command Physician for the PENNStar Flight Program at the Hospital of the University of Pennsylvania and is an Attending Physician at the Philadelphia Veterans Affairs Medical Center. Dr. Beers is a member of the Department of Medicine at the Perelman School of Medicine and participates in the Committee on Appointments and Promotions (COAP). He is also the Scientific Director of the PENN ILD Research Program and a member of the Perelman School of Medicine Core Research Facilities Oversight Committee. His educational background includes a B.A. in Biophysics and an M.D. from the University of Pennsylvania. His professional focus encompasses pulmonary medicine, with involvement in research, clinical care, and leadership within the academic medical community.

Research topics

• Biology
• Cell biology
• Genetics
• Computer Science
• Medicine
• Internal medicine
• Pathology
• Computational biology
• Virology
• Immunology

Selected publications

• Alveolar Type 2 Cell Dysfunction Is Associated with Bile Acid Alterations in Experimental Hepatopulmonary Syndrome

  American Journal of Respiratory Cell and Molecular Biology · 2026-03-27

  article

  Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis characterized by pulmonary microvascular dilation, hypoxemia, and increased mortality. Patients often exhibit unexplained restrictive ventilatory defects that correlate with circulating bile acids, suggesting superimposed alveolar dysfunction. To investigate this, we evaluated alveolar function, cell types, and the potential role of altered bile acids in the experimental HPS. Common bile duct ligation (CBDL) mice were assessed for pulmonary and surfactant function. AT2 cell-specific RiboTag RNA sequencing, single-cell RNA sequencing (scRNA-seq), and mass spectrometry-based bile acid profiling were performed. MLE12 cells were treated with bile acids in vitro, and an FXR agonist was administered in vivo to test effects on AT2 cell. CBDL mice developed HPS with restrictive defects due to reduced AT2 cell-derived surfactant-protein-C (SP-C), increased alveolar surface tension, and elevated plasma and bronchoalveolar bile acid levels. ScRNA-seq demonstrated a decrease in AT2 cells and an increase in AT2-to-AT1 transitional cells. AT2-specific RNA-seq revealed upregulated bile acid and cholesterol metabolism and downregulated proliferative pathways. In vitro, bile acids mimicking FXR antagonists reduced SP-C in MLE12 cells, while in vivo FXR agonist decreased circulating bile acids and restored SP-C-producing AT2 cells in CBDL mice. Our data demonstrates alterations in AT2 cell biology, including reduced surfactant expression, in the setting of elevated bile acids. These finding indicate an association between bile acid levels and AT2 cell alterations in cirrhosis and identify bile acid signaling and AT2 cell integrity as areas for future mechanistic investigation.

  PublisherDOI

• Divergent pathways of surfactant protein C maturation for disease-associated isoforms

  Journal of Biological Chemistry · 2026-02-05

  articleOpen accessSenior author

  in mouse lung epithelial-12 cells. Collectively, our data demonstrate that trafficking pathways for maturation of WT and mutant I73T SP-C diverge prior to the trans-Golgi network, where initial cleavage of the COOH-terminal SP-C propeptide occurs via a furin-like proprotein convertase.

  PublisherDOI

• Aging exacerbates checkpoint inhibitor pathway dysfunction in pulmonary fibrosis 3852

  The Journal of Immunology · 2025-11-01

  articleOpen accessSenior author

  Abstract Description Alveolar epithelial type 2 (AT2) cell reprogramming and senescence are hallmarks of pulmonary fibrosis (PF), a parenchymal lung disease more prevalent in aging individuals. We hypothesized that the PD-1/PD-L1 pathway, critical to immunosurveillance of many tissue niches, is exploited by fibrogenic AT2 to promote their persistence during fibrogenesis, worsening disease outcomes. In a clinically relevant, mouse model of spontaneous PF, aged (18-month) mice displayed a worse disease phenotype versus younger (3-month) cohorts characterized by increased weight loss, mortality, BALF cell counts and collagen burden accompanied by higher expression of senescence (Cdnkn1a; Cdnkn2a) and inflammatory (Ccl2; Tnfa) markers. Flow cytometry demonstrated increased accumulation of a CD51+, transitional AT2 population in older mice marked by enhanced PD-L1 levels. Additionally, lungs from older mice demonstrated increases in CD8+ and CD8+PD1+ T cells. Treatment of fibrotic aged mice with a PD-1/PD-L1 inhibitor (BMS-202) resulted in significantly reduced mortality along with decreases in BAL Sircol and improved static lung compliance. These findings suggests that aged mice exhibit a more severe fibrotic phenotype accompanied by alterations in re-programmed AT2 cell numbers and enhanced PD-1/PD-L1 synapses. We propose a model wherein pro-fibrotic epithelial populations escape immune surveillance avoiding clearance by CD8+PD1+ T cells to promote a fibrogenic niche. Funding Sources U01 HL152970 Topic Categories Immune Mechanisms of Human Disease (HUM)

  PublisherOA PDFDOI

• Releasing the Brakes in IPF: Inflammatory Fibroblasts Alter the Alveolar Niche to Promote Epithelial Expansion

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  articleSenior author

  Abstract Rationale: Application of single cell RNAseq (scRNAseq) in idiopathic pulmonary fibrosis (IPF) and multiple murine models has revealed two unique disease associated fibroblast subsets, the Cthrc1+ fibrotic population, and a population expressing inflammatory markers whose function is unclear. We, and others, have demonstrated that inflammatory fibroblasts are derived from homeostatic fibroblasts and can differentiate to Cthrc1+ fibroblasts. There is also data in mice suggesting that TGFβ inhibition prevents the emergence of Cthrc1+ fibrotic fibroblasts without impacting the inflammatory fibroblast population. Using our inducible genetic murine model of PF, reductionist organoid systems, and scRNAseq from IPF we present evidence and mechanism for inflammatory fibroblasts as a potential regenerative population in the alveolar niche. Methods: Tamoxifen administration to SftpcI73T conditional allelic knock-in mice, induces expression of mutant protein and promotes an inflammatory cascade followed by fibrogenesis. ScRNA-seq and population RNA-seq of bleomycin and SftpcI73T murine models were compared with publicly available data sets from IPF to identify population specific surface marker expression and potential epithelial ligand-receptor pairs. Flow cytometry approaches developed to isolate fibroblast populations were applied for in-vitro organoid modeling and validation of signaling pathways. In-vivo murine intervention in TGFβ signaling was further applied to confirm functional biology of inflammatory fibroblasts. Results: Informatic analysis of human and mouse inflammatory fibroblasts identifies expression of multiple BMP antagonists that have previously been associated with epithelial proliferation. Furthermore, human inflammatory fibroblasts also express key epithelial growth factors including FGF2 and FGF7. Murine organoid modeling confirms that inflammatory fibroblasts support alveolar organoid formation through the inhibition of BMP signaling. As was previously demonstrated in bleomycin, the inhibition of TGFβ signaling in SftpcI73T does not alter the inflammatory fibroblast population, rather this population is sustained, and alveolar epithelial proliferation increases. Additionally, we did not find any evidence for increase inflammation in the mouse lung due to inflammatory fibroblasts preservation. Finally, human data suggests that two populations of inflammatory fibroblasts are present in the lung with only one subset found to express the BMP antagonists and growth factors required to promote alveolar epithelial proliferation. Conclusions: Our data identifies that inflammatory fibroblasts in the alveolar niche inhibit BMP signaling and allow for epithelial expansion. We also determine differences between murine and human inflammatory fibroblasts suggesting that human inflammatory fibroblasts have a greater potential to drive epithelial expansion. These data shed light on the functional role of inflammatory fibroblasts, further refining our understanding of fibroblast heterogeneity in IPF.

  PublisherDOI

• Divergent Pathways of Surfactant Protein C Maturation for Disease-Associated Isoforms

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-04 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Surfactant Protein C (SP-C), a hydrophobic protein exclusively synthesized and secreted by alveolar type II (AT2) cells, is important for reducing alveolar surface tension in the distal lung. Chronic interstitial pulmonary diseases have been associated with SFTPC mutations. However, a detailed understanding of SP-C maturation in the secretory pathway and disruptions caused by mutations has remained incomplete. The goal of this study was to comprehensively ascertain differences in trafficking and post-translational processing between wild-type and disease-associated SP-C mutants using doxycycline-inducible mouse lung epithelial (MLE-12) cell lines expressing either wildtype SP-C or the common clinical variant SP-C I73T , validated using primary AT2 cells isolated from a murine SP-C I73T pulmonary fibrosis model and induced pluripotent stem cell (iPSC)-derived human alveolar type 2 cells (iAT2s) expressing the same mutant. In all 3 models SP-C WT was highly concentrated in acidic LROs while SP-C I73T accumulated on the plasma membrane, which was corroborated by inhibition of clathrin-mediated endocytosis, surface biotinylation, immunogold EM, immunofluorescent staining in non-permeabilized cells, and proteinase K protection assays supporting divergence of SP-C I73T trafficking from SP-C WT . The exclusion of SP-C I73T from normal routing occurred early in the biosynthetic pathway as Brefeldin A blocked processing of both SP-C proproteins, while a 20°C temperature shift caused selective accumulation of a processed proSP-C WT intermediate, suggesting initial C-terminal cleavage of proSP-C WT occurs in late-Golgi/ trans-Golgi network (TGN). This cleavage event was sensitive to DC1, an inhibitor of furin-related subtilisin-like proprotein convertase (PPC) family members. Site-directed mutagenesis of canonical residues K160, R167 within a predicted PPC recognition site in the proSP-C BRICHOS domain blocked its processing. Expression constructs encoding inhibitory pre-proprotein (pp) peptide fragments of Furin and ppPC7 each inhibited cleavage of proSP-C WT by MLE-12 cells. Collectively, our data demonstrate that trafficking pathways for maturation of WT and mutant I73T SP-C diverge prior to the TGN where initial cleavage of the COOH-terminal SP-C propeptide occurs via a Furin-like proprotein convertase.

  PublisherOA PDFDOI

• Deciphering the Dual Roles of IRE1α RNase and Kinase Activities in AT2 Cell Proteostasis and Pulmonary Fibrosis

  Physiology · 2025-05-01

  articleSenior author

  RATIONALE: The UPR regulator inositol-requiring enzyme 1 alpha (IRE1α) plays a central role in the fate of alveolar type 2 (AT2) epithelial cells with emerging evidence from our lab and others highlighting the potential of IRE1α inhibition to mitigate pathological AT2 states associated with lung fibrosis. IRE1α possesses dual enzymatic functions: 1) RNase activity, which splices X-box binding protein 1 (XBP1) mRNA into its active transcription factor form to promote adaptive responses, and 2) kinase activity, which can activate downstream stress signaling pathways such as JNK and caspase-3 cleavage, contributing to apoptosis. This study investigates specific roles of IRE1α RNase and kinase activity in AT2 proteostasis and their impact on injury and repair processes in models of pulmonary fibrosis. Methods: To interrogate IRE1α RNase and kinase activities, we used selective pharmacologic inhibitors in MLE12 cells under proteostatic stress: ORIN1001, an RNase-specific inhibitor, and SP600125, a JNK kinase inhibitor. Genetic validation was performed using kinase-dead/RNase-dead mutants overexpressed in IRE1α deficient MLE12s. IRE1α's RNase mediated activity was tested in vivo using a mouse model with AT2 cell-specific knockout of XBP1 subjected to bleomycin-induced lung injury. At day 21 post-bleomycin exposure we assayed for lung injury and physiology, inflammatory infiltrates, and collagen deposition. RNA and protein lysates from isolated AT2 cells were analyzed for markers of UPR pathways and XBP1-targets. The effects of XBP1 depletion on AT2 progenitor function was assessed using XBP1-deficient primary AT2 cells placed in feeder-free 3D cultures. Results: Pharmacologic or geneticinhibition of IRE1α kinase activity in MLE12 in vitro reduced pro-apoptotic signaling. Overexpression of constitutively active (spliced) XBP1 in MLE12 cells reduced terminal UPR signaling. Compared to wild-type controls, mice with AT2-specific XBP1 deletion exhibited increased susceptibility to bleomycin, as evidenced by impaired lung function, elevated BAL total protein and inflammatory cells, increased fibrillar and soluble collagen content as well as decreased total AT2 cell numbers. Ex vivo , XBP1-deficient AT2 cells demonstrated impaired proliferation, accompanied by reduced expression of molecular chaperones such as Erdj4, indicative of impaired proteostasis. Conclusions: While IRE1α's kinase activity promotes pro-apoptotic signaling via JNK activation, its RNase activity supports AT2 cell survival and proteostasis mediated by splicing of XBP1 mRNA. These findings underscore the importance of the IRE1α-XBP1 axis in AT2 cell health and suggest that selective modulation of this pathway may offer therapeutic potential for pulmonary fibrosis. Understanding distinct kinase and RNase activities of IRE1α is critical to developing targeted therapies that preserve adaptive UPR signaling while mitigating pro-fibrotic stress responses. NIH U01 HL145408, NIH T32 HL007586, and VA Merit 2I01BX001176-05 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• REGULATORY T CELLS PROTECT AGAINST ABERRANT REMODELING IN A MOUSE MODEL OF PULMONARY FIBROSIS

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-05

  preprintOpen accessSenior authorCorresponding

  Regulatory T (Treg) cells are well recognized for their role in immune regulation; however, their role in tissue regeneration is not fully understood. This study demonstrates such a role of Tregs in a published preclinical murine model of spontaneous pulmonary fibrosis (PF) expressing a human PF related mutation in the Surfactant Protein-C (SP-C) gene (SFTPCI73T). Genetic crosses of SP-CI73T mice with Foxp3GFP and Foxp3DTR lines were utilized to study Treg behavior during PF development. We found that FoxP3+Tregs accumulate during the transition from inflammation to fibrogenesis, peaking at 21-28 days after mutant SftpcI73T induction localizing to both perivascular and distal fibrotic lung regions. Diphtheria toxin mediated ablation of Tregs at 17 days worsened fibrosis and increased levels of TGFβ and inflammatory cytokines. Tregs expressed Th2 markers (Gata3+) and elaborated factors including amphiregulin (Areg) and Osteopontin (Spp1). Reductionist experiments showed that lung Tregs enhanced organoid formation when co-cultured with alveolar epithelial cells and adventitial fibroblasts, an effect size mimicked using Areg and Spp1 in combination. Our findings demonstrate that immune-mesenchymal-epithelial signaling crosstalk is present in the distal lung wherein Tregs play a protective role by limiting fibrosis and promoting tissue repair, highlighting their broader function beyond immune modulation in lung injury.

  PublisherOA PDFDOI

• Regulatory T cells protect against aberrant remodeling in a mouse model of pulmonary fibrosis

  Mucosal Immunology · 2025-12-27

  articleSenior author
  PublisherDOI

• Impaired AMPK control of alveolar epithelial cell metabolism promotes pulmonary fibrosis

  JCI Insight · 2025-07-01 · 7 citations

  articleOpen accessSenior author

  Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously demonstrated that expression of an AT2 cell-exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell-derived (iPSC-derived) AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here, using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 cell self-renewal and accumulation of transitional epithelial cells. We identify deficient AMPK signaling as a critical component of AT2 cell dysfunction and demonstrate that targeting this druggable signaling hub can rescue the aberrant AT2 cell metabolic phenotype and mitigate lung fibrosis in vivo.

  PublisherOA PDFDOI

• Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-28 · 3 citations

  preprintOpen accessSenior authorCorresponding

  Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.

  PublisherOA PDFDOI

Recent grants

• Surfactant Protein C Mutations and Interstitial Lung Disease

  NIH · 2012–2029

• Surfactant Protein C Mouse Models: A Fit For Purpose Preclinical Platform For Advancing Discovery In And Treatment Of Idiopathic Pulmonary Fibrosis

  NIH · $3.0M · 2021–2025

• NIH Grant R01HL064520

  NIH · $3.6M · 2010

• NIH Grant R01HL059867

  NIH · $1.6M · 2004

• Biosynthesis and Trafficking of Surfactant Protein C In Health and Disease

  NIH · $2.0M · 2013–2019

Frequent coauthors

• Yaniv Tomer

  University of Pennsylvania

  90 shared

• Elena N. Atochina‐Vasserman

  University of Pennsylvania

  67 shared

• Susan H. Guttentag

  Vanderbilt University

  65 shared

• Surafel Mulugeta

  University of Pennsylvania

  60 shared

• Jeremy Katzen

  University of Pennsylvania

  50 shared

• Andrew J. Gow

  Rutgers, The State University of New Jersey

  46 shared

• Scott J. Russo

  Icahn School of Medicine at Mount Sinai

  44 shared

• Philip L. Ballard

  Eunice Kennedy Shriver National Institute of Child Health and Human Development

  44 shared