Single-cell RNA-sequencing has transformed our understanding of alveolar epithelial type 2 (AT2) cells and alveolar lipofibroblasts (LIFs) during lung injury and repair. Both cell types undergo dynamic transitions through intermediate states that determine whether the lung proceeds toward regeneration or fibrosis. Emerging evidence highlights reciprocal paracrine signaling between AT2/AT1 transitional cells and LIF-derived myofibroblasts (aMYFs) as a key regulatory axis. Among these, amphiregulin (AREG)–EGFR signaling functions as a central profibrotic pathway whose inhibition can restore alveolar differentiation and repair. The human WI-38 fibroblast model provides a practical platform to study the reversible LIF–MYF switch and screen antifibrotic and pro-regenerative compounds. Candidate therapeutics including metformin, haloperidol and FGF10 show promise in reprogramming fibroblast and epithelial states through metabolic and signaling modulation. Integrating WI-38-based assays, alveolosphere co-cultures, and multi-omics profiling offers a translational framework for identifying interventions that halt fibrosis and actively induce lung regeneration. This review highlights a unifying framework in which epithelial and mesenchymal plasticity converge to define repair outcomes and identifies actionable targets for promoting alveolar regeneration in chronic lung disease.

Vascular remodeling is a prominent feature of pulmonary hypertension. This process involves increased muscularization of already muscularized vessels as well as neo-muscularization of non-muscularized vessels. The cell-of-origin of the newly formed vascular smooth muscle cells has been a subject of intense debate in recent years. Identifying these cells may have important clinical implications since it opens the door for attempts to therapeutically target the progenitor cells and/or reverse the differentiation of their progeny. In this context, the dominant model is that these cells derive from pre-existing smooth muscle cells that are activated in response to injury. In this mini review, we present the evidence that is in favor of this model and, at the same time, highlight other studies indicating that there are alternative cellular sources of vascular smooth muscle cells in pulmonary vascular remodeling.

Glioma-associated oncogene family zinc finger 1 (GLI1) encodes a major transcriptional effector of Hedgehog (HH) signaling. In adult tissues, GLI1 expression also marks perivascular mesenchymal populations with progenitor-like and injury-responsive properties. Over the past decade, lineage-tracing and single-cell studies in mice have shown that GLI1⁺ cells are not static: they may support vessel stability and repair, but they can also be recruited into maladaptive remodeling programs. For angiogenesis research, the key question is therefore not simply whether GLI1⁺ cells are present, but which state they adopt and what pushes them toward regeneration, fibrosis, neomuscularization, or tumor-supportive vasculature. Here, we synthesize how GLI1⁺ cells and GLI1 pathway activity intersect with endothelial, immune, mural-cell, and extracellular matrix (ECM) programs across physiological angiogenesis and major disease settings, including tumor angiogenesis, pulmonary vascular remodeling, and fibrotic vasculopathy. We also indicate where direct lineage-based evidence is available, where the evidence is still inferential, and which cell-state-specific nodes appear most realistic for therapeutic targeting.