Across more than fifteen years, research involving Prof. Yuben Moodley of the Institute for Respiratory Health in Perth, Australia, has approached this problem from strikingly different directions. One study asked whether stem cells could reduce scarring after severe lung injury. Another searched the blood of people with idiopathic pulmonary fibrosis for molecular clues that might reveal whose disease would worsen. A third examined a minute regulator of gene activity that appears both to signal progression and to suppress fibrotic behaviour. Together, the studies show how fibrosis research has moved from testing whole cells as potential therapies, through identifying patterns in circulating proteins, to investigating tiny packages carrying genetic regulators through the bloodstream.

The earliest of the three studies, published in 2009, focused on acute lung injury and the possibility of encouraging repair. Severe injury can set off inflammation, damage the barrier between air and blood, and eventually produce fibrosis. The researchers were interested in mesenchymal stem cells, versatile cells already attracting attention for their regenerative potential. Their particular source was Wharton’s jelly, the soft connective tissue surrounding the blood vessels of the human umbilical cord.

Umbilical cords offer practical advantages as a source of these cells. They are readily available after birth and obtaining them does not require an invasive bone marrow procedure. However, the important question was whether umbilical cord mesenchymal stem cells could actually change what happened inside an injured lung.

To investigate this, the team used mice in which the drug bleomycin produced lung injury and fibrosis. Twenty-four hours after the injury was induced, some animals received human umbilical cord mesenchymal stem cells through a vein. Other groups received saline or human lung fibroblasts, providing comparisons that helped the researchers distinguish a specific stem-cell effect from the simple introduction of human cells.

The results suggested something more interesting than straightforward replacement of damaged tissue. Two weeks after injection, the administered stem cells could be found in injured lungs, particularly around fibrotic areas, while they were not detected in healthy lungs treated with the cells. By four weeks, the injected cells were no longer detectable. Nor was there convincing evidence that they had transformed into the specialised lung cells responsible for lining the air sacs.

Instead, their benefit appeared to come from changing the environment in which injury and repair were taking place. The treated lungs showed less inflammation and lower activity of several signals associated with inflammation and fibrosis. Particularly important was transforming growth factor beta, a powerful driver of scarring. Activity in its signalling pathway was reduced. The amount of collagen, a major structural component of scar tissue, was also significantly lower.

The stem cells seemed to influence both how much scar material was produced and the machinery capable of breaking that material down. Levels of matrix metalloproteinase-2, an enzyme involved in degrading components of the surrounding tissue matrix, increased, while natural inhibitors of such enzymes decreased. The balance therefore shifted towards an environment more favourable to removing deposited collagen. Human lung fibroblasts used as a control did not reproduce these effects.

The experiment suggested that a regenerative cell therapy need not rebuild a damaged lung by physically becoming new lung tissue. Cells might instead act more like temporary biological coordinators, arriving at an injury and altering the chemical conversation around them. That idea opens a broader way of thinking about repair. A useful intervention might work by quietening signals that promote scarring while encouraging processes that dismantle excessive matrix.

There were, of course, important boundaries around what this experiment could establish. It was conducted in mice, using bleomycin to create injury. However, this work underpinned clinical trials in human subjects. These cells were used in ventilated patients with Covid who suffered respiratory failure. They were shown to be safe but were not uniformly effective. There are several case studies that have shown these cells have benefited individual patients that have pulmonary fibrosis with an acute exacerbation. The overall efficacy in a large group of patients remains unclear. The cells were also administered very early, only a day after injury. That is different from treating a person whose fibrotic disease has already become established. Still, the study identified biological pathways that could be influenced and offered evidence that fibrosis was not simply an irreversible endpoint.

That question becomes even more pressing in idiopathic pulmonary fibrosis, or IPF. Unlike an acute injury with an obvious starting point, IPF is a chronic disease whose cause is unknown and whose course can vary dramatically from person to person. Some patients remain relatively stable for a time, while others deteriorate rapidly. Clinicians therefore face a second challenge alongside finding better treatments: knowing, as early as possible, which path an individual patient is likely to follow.

More than a decade after the stem-cell study, Moodley and colleagues turned to the bloodstream for clues. Rather than asking how an experimental treatment might alter fibrosis, they asked whether molecules already circulating in patients could reveal the future behaviour of the disease. The shift in scale was profound, but the underlying goal remained connected: understand the biology of harmful scarring well enough to intervene more intelligently.

The 2022 study began with a powerful idea: blood carries traces of what is happening elsewhere in the body. If fibrosis and tissue injury alter particular circulating molecules, a blood sample might provide an early warning that IPF is becoming more aggressive.

The researchers examined three independent groups of people with IPF from Australia and the United Kingdom, comparing molecular signals in patients whose disease progressed within a year with those whose condition remained stable.

Their search highlighted four proteins: osteopontin, matrix metalloproteinase-7, intercellular adhesion molecule-1 and periostin. These are involved with processes including epithelial injury, fibroblast activity, matrix deposition and inflammation. Rather than treating one molecule as a perfect crystal ball, the researchers combined all four into a progression index.

That approach reflects the complexity of IPF, which is unlikely to be captured by a single measurement. Combining signals creates a broader molecular snapshot. Tested across separate patient cohorts, the progression index was associated with progression, mortality and progression-free survival. Molecular information could also improve prediction beyond a clinical score based on gender, age and lung physiology.

The significance is practical as well as scientific. Lung function tests are indispensable, but deterioration may reflect damage that has already occurred. A reliable blood-based warning system could potentially identify higher-risk patients earlier and inform clinical decisions. The study did not produce a finished test ready for routine use, but demonstrated that the circulation contains a measurable molecular signature of disease behaviour.

That idea forms a direct bridge to the most recent of the three studies. Blood contains more than freely circulating proteins. It also carries tiny membrane-bound parcels called small extracellular vesicles. Cells release these packages into their surroundings, and the vesicles can transport molecular cargo between cells. Among that cargo are microRNAs, remarkably small molecules capable of influencing which proteins cells produce.

MicroRNAs regulate gene expression by interacting with messenger RNA, the instructions used to make proteins, rather than encoding proteins themselves. In fibrosis, changing genes involved in collagen production and growth-factor signalling can help determine whether repair remains controlled or tips towards persistent scarring.

In the 2025 study, Prof. Moodley and colleagues investigated microRNAs carried within small extracellular vesicles in the blood of people with progressive and stable IPF. Their screening led them to a microRNA called let-7f-5p. In an Australian group, progressive disease was associated with a tendency towards lower levels of this microRNA, with a clearer reduction among patients whose capacity to transfer gases from the lungs into the blood had declined substantially. In a separate American cohort, let-7f-5p was also significantly lower in patients with progressive disease.

The researchers then asked whether reduced let-7f-5p merely signalled worsening disease or could itself influence fibrosis. To explore this, they introduced a let-7f-5p mimic into primary lung fibroblasts, including cells from people with IPF. When activated into myofibroblasts, these cells produce collagen and contribute to fibrotic stiffening.

Increasing let-7f-5p changed that behaviour. The treated cells produced less of key markers associated with myofibroblast activity and collagen formation. The researchers also observed reduced expression of a receptor for transforming growth factor beta, returning to a signalling pathway that had featured prominently in the stem-cell work many years earlier. Another change involved increased expression of SOCS3, a regulator associated with restraining processes involved in fibrosis.

This creates an intriguing connection across the three studies. The 2009 research showed that umbilical cord cells could alter a fibrotic environment. The 2022 work showed that circulating molecules could help distinguish more aggressive IPF. The 2025 study brought those themes together by identifying a molecule that might be both a marker of progression and an active participant in controlling fibrosis.

There is still a substantial distance between these findings and a new treatment. A microRNA mimic that changes fibroblasts in a laboratory dish is not automatically a safe or effective medicine. Delivering it to the right cells in human lungs and avoiding unwanted effects would require extensive investigation.

Progress in difficult diseases rarely arrives as one dramatic discovery. It is built by asking better questions at different scales. Can injured lung tissue repair differently? Can blood reveal deterioration earlier? Can a signal of progression also expose a mechanism that might be therapeutically altered?

Across these studies, fibrosis emerges as the outcome of an active and potentially influenceable biological conversation. Cells respond to injury, proteins carry evidence of disease activity, extracellular vesicles transport regulatory messages, and microRNAs help decide which genetic instructions are followed.

For patients with IPF, the long-term hope is to turn that growing knowledge into two things medicine urgently needs: earlier foresight and more precise intervention. The ability to predict progression could reveal when action is most needed, while understanding the molecular machinery of fibrosis could reveal where to act. From stem cells to blood proteins to microscopic packages of RNA, the work traces a continuing effort to give damaged lungs something they desperately need: more breathing room.