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
Yu Zhong, Biao Wei, Wenbiao Wang, Junzhe Chen, Wenjing Wu, Liying Liang, Xiao-Ru Huang, Cheuk‐Chun Szeto, Xueqing Yu, David J. Nikolic‐Paterson, Hui-Yao Lan
Abstract
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 (-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 sex-mismatched kidney transplants by the discovery that ECM-producing cells originated from recipient, not donor, bone marrow-derived progenitor cells (BMPCs).Moreover, these BMPCs-derived 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.