The stakes of the review are considerable. Organ fibrosis, the end result of chronically dysregulated tissue repair, is estimated to account for roughly 45 percent of all deaths worldwide, spanning conditions as diverse as idiopathic pulmonary fibrosis, cirrhosis, chronic kidney disease, and post-infarction cardiac scarring. Despite its enormous clinical burden, there are currently no treatments that reliably reverse established fibrosis; existing therapies such as nintedanib, pirfenidone, and resmetirom slow progression at best. By mapping the immune landscape of fibrosis at single-cell and single-cell-location resolution, the review’s authors argue that macrophages represent the most promising lever for precision interventions—and that the field’s failure to exploit their heterogeneity has been a key reason anti-fibrotic drug development has repeatedly stalled.

The technical foundation for this reappraisal is the maturation of single-cell RNA sequencing, single-nucleus RNA sequencing, and spatial transcriptomics. These platforms allow investigators to profile thousands of individual cells from fibrotic tissue, cluster them by their transcriptional identities, and then place those identities back into their anatomical context within the scarred organ. What these tools have revealed is that macrophages within a single fibrotic organ are not a uniform population responding uniformly to inflammation. Instead, they occupy a multidimensional landscape defined by at least four axes: their cellular origin, the stage of disease at which they are sampled, the spatial microenvironment they inhabit, and their ultimate functional output, whether that output is collagen deposition, matrix degradation, or efferocytosis—the clearance of dead cells.

The origin axis is particularly consequential. Tissue-resident macrophages in organs such as the lung, liver, and brain are embryonically derived, seeding tissues during development from yolk sac and fetal liver progenitors and thereafter maintaining themselves locally through self-renewal. In the liver, these resident cells are the Kupffer cells, which patrol the sinusoids and perform surveillance functions honed over a lifetime. By contrast, when injury strikes, bone marrow-derived monocytes flood into the damaged organ in response to chemokine gradients—chiefly the CCL2/CCR2 axis—and differentiate into monocyte-derived macrophages with fundamentally different transcriptional programs. Fate-mapping studies using markers such as Ms4a3 have allowed researchers to distinguish these lineages with precision, and the distinction matters therapeutically: in the lung, monocyte-derived alveolar macrophages have been shown to drive fibrosis and persist in tissue over the lifespan of the animal, whereas resident alveolar macrophages generally perform homeostatic and restorative functions.

Nowhere is the new heterogeneity framework more vividly illustrated than in the identification of SPP1-expressing macrophages. Secreted Phosphoprotein 1, also known as osteopontin, marks a subset of stroma-associated macrophages that the review identifies as a conserved pro-fibrotic end-state across all four organs examined. In the lung, proliferating SPP1/MERTK-expressing macrophages have been documented in idiopathic pulmonary fibrosis. In the kidney, platelet-instructed SPP1-positive macrophages drive myofibroblast activation in a CXCL4-dependent manner. In the heart, spatial multi-omic maps of human myocardial infarction have localized these cells to the infarct border zone, where they sit alongside activated fibroblasts in a self-reinforcing signaling loop. The review’s authors propose that SPP1-positive macrophages, because they recur in fibrotic niches across organ boundaries, could serve as a candidate cross-organ therapeutic axis—meaning a drug developed against this cell type in one organ might conceivably be repurposed for fibrotic diseases elsewhere in the body.

Spatial transcriptomics has been essential to identifying these conserved niches because it reveals not just which cells are present, but where they are relative to their targets. Scar-associated macrophages, for example, are not scattered randomly through fibrotic tissue; they cluster adjacent to myofibroblasts, the collagen-producing workhorses of fibrosis, in spatially restricted niches sustained by growth factors such as macrophage colony-stimulating factor. In the heart, CCR2-positive and CCR2-negative resident macrophages perform distinct roles in orchestrating monocyte recruitment after myocardial injury, and their positioning within the infarct zone versus the border zone correlates with different outcomes for tissue remodeling. The spatial dimension transforms macrophage biology from a cell-autonomous story into an ecological one: macrophages behave differently depending on which neighbors they are talking to.

The review also devotes substantial attention to the metabolic reprogramming that underlies macrophage fate decisions—a dimension of immunology that has accelerated dramatically since the recognition that activated immune cells undergo profound shifts in fuel preference. Classically activated pro-inflammatory macrophages rely on aerobic glycolysis, a Warburg-like metabolic state that prioritizes rapid ATP generation and biosynthetic intermediates over mitochondrial efficiency. The glycolysis–PKM2 axis, in which Pyruvate Kinase Isozyme Type M2 acts as both a metabolic enzyme and a transcriptional co-activator of HIF-1α-driven inflammatory genes, has emerged as a central switch in this process. In the kidney, myeloid PFKFB3-mediated glycolysis has been shown to promote fibrosis, and pharmacological inhibition of PFKFB3 attenuates disease in experimental models. In the heart, temporal changes in glucose metabolism reflect polarization shifts in resident and monocyte-derived macrophages after myocardial infarction, offering a metabolic readout of the transition from inflammatory to reparative phases.

Metabolism does not merely fuel macrophages; it determines what they become. The review highlights how succinate, an intermediate of the tricarboxylic acid cycle, functions as a signaling molecule through its receptor SUCNR1 to induce profibrotic M2-like macrophages in the kidney, yet exerts protective effects on hepatocytes in the context of non-alcoholic fatty liver disease. This context-dependence—where the same metabolite promotes pathology in one organ and protects in another—illustrates why the review’s authors caution against oversimplified cross-organ generalizations even as they identify conserved subsets like SPP1-positive macrophages. Similarly, the c-Rel transcription factor has been shown to orchestrate energy-dependent reprogramming in both epithelial cells and macrophages during fibrosis, linking mitochondrial metabolism to the epigenetic regulation of inflammatory gene expression.

On the therapeutic front, the review surveys an expanding toolkit for manipulating macrophages in fibrotic disease. Rather than depleting all macrophages—a strategy that risks impairing essential homeostatic and reparative functions—emerging approaches aim for precision. Selective depletion of profibrotic macrophages using bioactivated in-vivo self-assembly peptides has been shown to ameliorate kidney fibrosis in experimental models while sparing beneficial populations. Therapeutic silencing of Spp1 specifically within TREM2-positive cardiac macrophages has been demonstrated to suppress atrial fibrillation. Nanoengineered immunosuppressive therapeutics, including dendrimer-graphite nanoparticles and endogenous cell-targeting nanoplatforms, are being explored for their ability to modulate the balance of macrophage phenotypes in situ rather than eliminating cells outright. Reprogramming strategies—shifting macrophage polarization away from profibrotic states using agents such as the FXR agonist resmetirom, which recently completed a Phase 3 trial in metabolic dysfunction-associated steatohepatitis—represent another layer of intervention that exploits metabolic vulnerabilities.

Chemokine axis blockade remains a parallel strategy. The CCR2/CCR5 dual inhibitor cenicriviroc, originally investigated for its ability to reduce inflammatory monocyte recruitment to the liver in steatohepatitis, has been re-examined in the context of COVID-19-associated lung injury, while inhibitors targeting PSMP/MSMP through CCR2 represent novel antifibrotic targets identified in hepatology. The review also underscores the significance of macrophage-to-myofibroblast transition, or MMT, in which macrophages themselves acquire collagen-producing characteristics—a phenomenon documented in renal fibrosis via the neural transcription factor Pou4f1 and in kidney disease through myofibroblast-derived exosomal signaling. Blocking these transdifferentiation pathways, rather than simply modulating polarization, adds a third dimension to the therapeutic landscape.

The authors argue that understanding macrophage heterogeneity as a multidimensional phenomenon—shaped simultaneously by origin, disease stage, spatial context, and metabolic state—will be necessary to design interventions that can navigate this complexity rather than being defeated by it. They highlight that organ-specific macrophage biology remains non-uniform despite the identification of conserved subsets, and that therapeutic strategies calibrated to a single axis of heterogeneity risk incompletely modulating disease. In liver fibrosis, for example, splenocyte-derived macrophages traveling through a spleen–liver axis exacerbate scarring independently of bone marrow-derived recruitment, adding yet another anatomical layer to macrophage origins that must be considered. In lung fibrosis, interstitial macrophages and alveolar macrophages represent distinct compartments with distinct functional roles, and treatments must account for both. In cardiac fibrosis, macrophage-derived CCL24 signaling through fibroblast CCR3 has been identified as a driver of pathological remodeling, while MMP-12-producing Ly6C-low macrophages paradoxically extend post-infarction survival by preventing neutrophil influx—underscoring that macrophages cannot be uniformly classified as friend or foe.

What the review ultimately advances is a conceptual reframing. Fibrosis research has historically sought a single target or a single pathway that could be inhibited across all patients. The single-cell omics era, as synthesized here, argues instead for precision strategies tailored to the specific macrophage subtypes and microenvironmental niches operating in a given patient’s disease at a given stage. The identification of SPP1-positive macrophages as a conserved, targetable, pro-fibrotic end-state across lung, liver, kidney, and heart offers one candidate for such a strategy, while the growing catalog of metabolic checkpoints—PKM2, PFKFB3, SUCNR1, and c-Rel—provides pharmacological handles for shifting macrophage behavior without destroying these essential cells. Whether this framework can be translated into clinical interventions that meaningfully reverse, rather than merely slow, organ fibrosis remains the defining challenge of the next decade of fibrosis research, but the review makes clear that the macrophage, in all its staggering diversity, is now the center of that effort.

Lung development is a marvel of coordinated cellular choreography, requiring precisely timed communication between various cell types to establish the complex architecture and functionality necessary for respiration. Traditionally, epithelial cells, which line the airways, and mesenchymal cells, a heterogeneous group that provides structural support and niche signals, were studied separately regarding their roles in development and pathology. However, this study illuminates how these two cell populations engage in direct competition, influencing each other’s destiny to balance organ formation with repair mechanisms.

Delving deeply into embryonic lung tissues as well as models of adult lung fibrosis, the researchers utilized advanced lineage tracing and single-cell transcriptomics to dissect the molecular dialogs underpinning this competition. They demonstrated that epithelial and mesenchymal cells do not merely coexist but actively contest spatial domains and functional roles through signaling pathways that regulate proliferation, differentiation, and apoptosis. This dynamic competition ensures that tissue compartments are populated with the appropriate cell types in response to developmental cues and injury.

Of particular interest is the identification of a regulatory network mediated by Notch and Wnt signaling pathways, which modulate the competitive interactions. The epithelial cells, expressing specific Notch ligands, can inhibit mesenchymal expansion under normal conditions, maintaining tissue boundaries and promoting epithelial integrity. Conversely, under fibrotic stress or injury, mesenchymal cells can alter their signaling output, tipping the balance to favor fibrotic tissue deposition and impaired epithelial regeneration.

Furthermore, the study highlights how mechanical forces and extracellular matrix components influence this cellular rivalry. Mesenchymal cells, by remodeling the local matrix, can create a microenvironment that either supports epithelial proliferation or drives fibrotic scarring depending on the context. This mechanotransduction aspect introduces a critical layer of complexity, integrating biochemical cues with physical interactions to precisely regulate lung tissue composition.

Importantly, the authors report that disrupting this epithelial-mesenchymal cell competition in mouse models leads to aberrant lung development characterized by defective airway patterning and compromised alveolarization. Similarly, in models of lung fibrosis, abnormal competition accelerates scar formation and decreases tissue elasticity—a hallmark of diseases such as idiopathic pulmonary fibrosis (IPF). These findings underscore the pathological implications of dysregulated cell fate decisions in chronic lung conditions.

The implications for regenerative medicine and anti-fibrotic therapy are profound. Understanding the molecular switches controlling epithelial and mesenchymal fate could enable targeted interventions that restore healthy competition balance, thereby promoting tissue repair while mitigating fibrosis. For example, modulating Notch or Wnt pathways, or targeting extracellular matrix remodeling enzymes, may recalibrate cellular interactions toward regenerative outcomes.

Technological advances, including single-cell RNA sequencing with spatial transcriptomics, were instrumental in illuminating the heterogeneous cell populations and their dynamic states within lung tissue compartments. These data suggest that epithelial and mesenchymal cells exist on a spectrum of activation states rather than discrete identities, further complicating but also enriching our understanding of their interactions. This continuum model could explain variable responses to injury and treatment observed in patients.

This study also propels the concept that tissue compartments in the lung are not static territories but fluid domains maintained by cellular competition and signaling gradients. Such dynamic regulation allows lungs to adapt to developmental and environmental changes but also opens vulnerabilities when homeostatic mechanisms fail. The competitive cellular crosstalk thus serves as a fundamental principle underpinning organ plasticity and disease progression.

Elucidating how epithelial and mesenchymal cells interpret and respond to in vivo signals during lung development sets a precedent for exploring similar competitive mechanisms in other organs prone to fibrotic diseases, such as the liver or kidney. The conserved nature of these pathways might suggest universal principles of tissue maintenance and repair that transcend organ-specific contexts, broadening the scope of potential interventions.

In their meticulous work combining developmental biology, cell signaling, and pathological models, the authors propose a new paradigm whereby cell competition is not merely a developmental curiosity but a critical determinant of organ health and disease. This insight challenges previous compartmentalized views and invites a holistic perspective on cell fate regulation within tissue ecosystems.

As next steps, the research community is expected to probe how external factors such as aging, pollution, and infection might perturb epithelial-mesenchymal cell competition. Deciphering these influences will be crucial for understanding the onset and progression of chronic lung diseases, many of which currently lack effective therapies. The interplay between genetic predisposition and environmental insults in modulating this cellular competition represents an exciting frontier.

The advent of novel imaging technologies and organoid models derived from patient cells will likely accelerate translational research by enabling precise manipulation of epithelial and mesenchymal interactions ex vivo. Such platforms will be invaluable for screening potential drugs that can restore healthy competition, offering hope for personalized approaches to lung fibrosis and regenerative medicine.

This landmark study by Klinkhammer, Warren, Knopp, and their team not only advances our fundamental knowledge of lung biology but also offers a compelling narrative of how cells communicate and compete to sculpt functional tissues. Their findings illuminate the delicate balance of cellular power struggles that sustain life and open transformative possibilities for treating devastating lung diseases.

As the global burden of fibrotic lung conditions rises, fueled by aging populations and environmental challenges, insights into epithelial-mesenchymal competition stand poised to inspire a new generation of therapies. By harnessing the natural competitive dynamics within tissues, future treatments may pioneer innovative regenerative strategies, shifting paradigms from symptom management to true biological cure.

The scientific community eagerly awaits further studies building upon these findings to decode the complexities of cell competition and guide clinical breakthroughs. The potential to intervene at the level of cell-cell interactions offers a promising horizon for lung disease research, embodying the concept that understanding and modulating fundamental biological processes can profoundly impact human health.

Subject of Research: The study explores the dynamic competition between epithelial and mesenchymal cells that governs fate decisions during lung development and fibrosis, revealing how these cellular interactions regulate tissue compartmentalization and remodeling.

Article Title: Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis.

Article References:
Klinkhammer, K., Warren, R., Knopp, J. et al. Epithelial-mesenchymal cell competition coordinates fate transitions across tissue compartments during lung development and fibrosis. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66690-z

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