Division of Nephrology and Clinical Immunology, RWTH Aachen University, Aachen, Germany.
Division of Nephrology, Department of Medicine and Department of Cell Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
JCI Insight. 2018 May 3;3(9):99561. doi: 10.1172/jci.insight.99561.
Fibrosis is the common final pathway of virtually all chronic injury to the kidney. While it is well accepted that myofibroblasts are the scar-producing cells in the kidney, their cellular origin is still hotly debated. The relative contribution of proximal tubular epithelium and circulating cells, including mesenchymal stem cells, macrophages, and fibrocytes, to the myofibroblast pool remains highly controversial. Using inducible genetic fate tracing of proximal tubular epithelium, we confirm that the proximal tubule does not contribute to the myofibroblast pool. However, in parabiosis models in which one parabiont is genetically labeled and the other is unlabeled and undergoes kidney fibrosis, we demonstrate that a small fraction of genetically labeled renal myofibroblasts derive from the circulation. Single-cell RNA sequencing confirms this finding but indicates that these cells are circulating monocytes, express few extracellular matrix or other myofibroblast genes, and express many proinflammatory cytokines. We conclude that this small circulating myofibroblast progenitor population contributes to renal fibrosis by paracrine rather than direct mechanisms.
纤维化是几乎所有慢性肾脏损伤的共同最终途径。虽然肌成纤维细胞是肾脏中产生疤痕的细胞已被广泛接受，但它们的细胞来源仍存在激烈争议。近端肾小管上皮细胞和循环细胞（包括间充质干细胞、巨噬细胞和成纤维细胞）对肌成纤维细胞池的相对贡献仍存在很大争议。通过诱导性遗传命运追踪近端肾小管上皮细胞，我们证实近端小管不会产生肌成纤维细胞池。然而，在联体共生模型中，一个联体共生体的遗传标记，而另一个未标记并发生肾脏纤维化，我们证明一小部分遗传标记的肾脏肌成纤维细胞来自循环。单细胞 RNA 测序证实了这一发现，但表明这些细胞是循环单核细胞，表达很少的细胞外基质或其他肌成纤维细胞基因，并且表达许多促炎细胞因子。我们的结论是，这个小的循环肌成纤维细胞祖细胞群体通过旁分泌而不是直接机制促进肾脏纤维化。
