Single-Cell RNA-Sequencing Identifies Bone Marrow-Derived Progenitor Cells as a Main Source of Extracellular Matrix-Producing Cells Across Multiple Organ-Based Fibrotic Diseases

Fibrosis is characterized by the aberrant deposition of extracellular matrix (ECM) due to dysregulated tissue repair responses, imposing a significant global burden on fibrosis-related diseases. Although alpha-smooth muscle actin (alpha-SMA/ACTA2)-expressing myofibroblasts are considered as key player in fibrogenesis, the origin of ECM-producing cells remains controversial. To address this issue, we integrated and analyzed large-scale single-cell transcriptomic datasets from patients with distinct fibrotic diseases involving the heart, lung, liver, or kidney. Unexpectedly, not all ACTA2-expressing cells were ECM-producing cells identified by expressing collagen genes; instead, the majority of ECM-producing cells were myofibroblasts and fibroblasts derived from circulating bone marrow precursor, and to a lesser extent from local pericytes and vascular smooth cells in all fibrotic diseases. This was confirmed in the sex-mismatched kidney transplants with the finding of recipient but not donor origin of bone marrow ECM-producing cells exhibited a proinflammatory phenotype. Thus, bone marrow-derived proinflammatory and profibrotic fibroblasts/myofibroblasts with stem cell properties serve as a major source of ECM-producing cells and may play a driving role in tissue fibrosis across a wide range of human fibrotic diseases. Targeting these ECM-producing cells may provide a novel therapy for diseases with fibrosis.