Pro-Fibrotic Factor in Mesenchymal Stem Cells Seen to Trigger Anti-Fibrotic Response
Mesenchymal stem cells can aid in treating autoimmune-related lung fibrosis by changing the composition of T-cells from a mainly toxic to a more regulatory type. The beneficial effects observed in the study were induced by the surprising contribution of TGF-β1 — a molecule normally considered strongly pro-fibrotic, indicating that treatments selectively targeting specific T-cell subtypes might perform better than those that suppress these immune cells.
Interstitial pneumonia — or inflammation of the tissue surrounding lung alveoli — affects patients with both idiopathic pulmonary fibrosis and connective tissue diseases, and could lead to increased fibrosis.
Researchers have still not mapped out which immune cell types drive the fibrotic process, and some studies indicate that mouse models of lung fibrosis do not adequately capture the molecular aspects of fibrotic disease.
A team from the Guangzhou Medical University set out to explore molecular and cellular contributions to disease processes by analyzing lung and blood samples, along with cells isolated from bronchoalveolar lavage fluid from 28 patients with autoimmune connective tissue disease and 23 control individuals.
Study results, published in the journal Stem Cell Research & Therapy, showed a high proportion of cytotoxic T-cells in both blood and lung tissue from the patients. The levels of regulatory T-cells (Tregs), known to harness inflammatory processes, were also lower in patients than in the controls.
As part of the study, “Immunomodulation by mesenchymal stem cells in treating human autoimmune disease-associated lung fibrosis,“ researchers isolated human lung fibroblasts and studied them in the lab. These cells released larger amounts of pro-inflammatory cytokines — immune signaling molecules known to drive inflammation and fibrosis. When normal fibroblasts were stimulated with these cytokines, in particular IL-6, they started taking on a fibrosis-promoting appearance.
As recent reports have shown that mesenchymal stem cells — derived from bone marrow of adult individuals — have the potential to interfere with autoimmune processes and promote the repair of lung alveoli, researchers also investigated the impact of the addition of stem cells to T-cells and fibroblasts in culture.
Mesenchymal stem cells were found to increase the proportion of Tregs while reducing cytotoxic cells, to lower the levels of pro-inflammatory cytokines and prevent pro-fibrotic changes. The team noted that mesenchymal cells secreting high levels of the molecule TGF-β1 had the most potent anti-fibrotic effects.
Considering that TGF-β is among the factors most strongly driving fibrotic processes, the researchers looked further into this surprising finding, and noted that fibroblasts from patients reacted differently to TGF-β in comparison to fibroblasts isolated from healthy controls.
This finding was strengthened by treating fibrotic mice with the medium the stem cells were grown in. Culture medium containing high levels of TGF-β reduced lung inflammation and fibrosis, and prolonged survival more than culture medium with low levels of the factor.
Results indicated that mesenchymal stem cell-based therapy may be beneficial by increasing Tregs and decreasing cytotoxic T-cells, compared to therapies that block all types of T-cells.