Umbilical Cord Stem Cells Hold Potential in PF Treatment

Small extracellular vesicles (EVs) released from umbilical cord stem cells seem to carry molecules that can inhibit the TGF-beta signaling pathway and reduce tissue damage in the lungs of mice with pulmonary fibrosis (PF), a study shows.

The findings support further research on stem cell-derived EVs as a potential treatment for PF.

The study, “Extracellular vesicles derived from umbilical cord mesenchymal stromal cells alleviate pulmonary fibrosis by means of transforming growth factor-β signaling inhibition,” was published in Stem Cell Research & Therapy.

PF is characterized by scarring (fibrosis) in the lungs, which is the result of excessive formation of extracellular matrix components such as collagen. When the lining of the alveoli, where gas exchange takes place in the lungs, is harmed, the TGF-beta signaling pathway is activated, leading to the production of alpha-smooth muscle actin (alpha-SMA) and collagen.

Recently, mesenchymal stem cells (MSCs) have received increasing attention because of their anti-fibrotic properties. Their beneficial effects are believed to be mediated in part by the release of tiny particles, called EVs, that carry information to other cells. EVs are vital for a wide range of cell functions and they have been linked to the development of idiopathic PF.

A group of researchers from China hypothesized that extracellular vesicles from umbilical cord-derived MSCs could be used to target the TGF-beta signaling pathway and block lung fibrosis in a mouse model of PF. These stem cells were selected because of their better proliferation and differentiation abilities compared to MSCs.

“MSCs are usually obtained from the adult bone marrow, umbilical cord blood, adipose tissue, and placenta. However, the differentiation potential of MSCs decreases as the donor’s age increases, limiting their applications,” the researchers wrote. “Umbilical cord-derived MSCs (uMSCs) have high cell differentiation abilities and thus are preferred for transplantation in this regard.”

PF mice were treated with uMSC or uMSC-EVs.

Results showed that uMSC and uMSC-EVs-treated mice had increased survival rates, and reduced lung tissue damage and collagen deposition compared with untreated mice. As expected, the fibrotic markers alpha-SMA and Fn where highly expressed in the lungs of PF mice; however, treatment with uMSC and uMSC-EV reduced the expression levels of these two genes.

Researchers also showed that uMSC-EVs could inhibit the production of alpha-SMA by myofibroblast cells — a cell type essential for wound healing and involved in fibrosis.

The “results suggest that uMSC-EVs can inhibit myofibroblast differentiation likely through inhibiting the TGF-[beta] signaling pathway in the lung tissue of PF mice,” the researchers wrote.

MicroRNAs (miRNAs), small RNA molecules that can control the expression of several genes, have recently been implicated in PF. Thus, the team investigated whether miRNAs, carried by uMSC-EVs, could be responsible for the inhibition of myofibroblasts.

Five miRNAs were found to be highly expressed in uMSC-EVs and their target genes were predicted using online databases. The microRNA miR-21-5p was found to directly target TGF-beta 2, while miR-23-3p inhibits the receptor TGF-beta R2.

Next, the silencing abilities of these two miRNAs were evaluated in vitro. Myofibroblasts were incubated with miR-21-5p or miR-23-3p and their effects on the expression of TGF-beta 2 and TGF-beta R2 were confirmed, as well as their ability to reduce alpha-SMA expression.

“We found that miR-21 and miR-23, which are highly enriched in uMSC-EVs, played a critical role in inhibiting TGF-[beta]” signaling, the researchers wrote.

The team, however, highlighted a few study limitations. For example, MSCs also have immunomodulatory effects, including the ability to induce immune cells, as well as to produce anti-inflammatory cytokines. Whether uMSC-EVs have these effects was not investigated. Additionally, factors such optimal dosage of EVs, timing, and delivery route still have to be determined and optimized.

Nonetheless, based on the results, the team concluded that uMSCs have therapeutic potential in PF, and that “the effects of uMSCs on PF alleviation are likely achieved via EVs, which reveals a new role of uMSC-EV-derived miRNAs, opening a novel strategy for PF treatment in the clinical setting,” they wrote.