A ‘handbook’ to fast-track breakthroughs in scarring research

Pinpointing the precise culprits behind harmful biological processes—such as excessive scarring (fibrosis) in organs like the kidneys and lungs—has long remained challenging even though this affects almost a billion people worldwide. But thanks to the emergence of single-cell isolation technologies, researchers have been able to zero in on the specific immune cells causing trouble.

In a comprehensive review published in Nature Reviews Immunology, a Duke-NUS-led team compiled a “handbook” of key insights from over 200 studies on immune cell types, their location and their behavioral changes over time, providing an evidence-based start line to accelerate scarring research.

Their start line points to the changeable behavior of a type of immune cell, called macrophage, that has emerged as a key driver of excessive scarring.

“Think of macrophages as having ‘happy’ faces, promoting healthy tissue repair, or ‘angry’ faces, causing harmful scarring. Recent technological advances have made it possible to identify exactly which cells trigger fibrosis, opening new doors for targeted treatments,” said Associate Professor Jacques Behmoaras from Duke-NUS’ Cardiovascular and Metabolic Disorders Program, the corresponding author of the review paper.

But what are these instigators of fibrosis like? How do they function and interact with the environment around them? And is there any way to prevent them from harming the body?

Since the first study involving single-cell transcriptomics was published in 2009, scientists have come closer than before to fully answering these questions by observing macrophages from a spatial and temporal perspective.

In their summary of these findings, Assoc Prof Behmoaras and his team highlight the following crucial discoveries:

• Macrophages vary depending on their environment: Using the single-cell RNA sequencing technique, researchers have constructed atlases that map cells across the various organs in the human body. These human cell atlases have shown that macrophages express different characteristics depending on their locations—for instance, lung macrophages bear the PPARG gene while those found in the kidney bear the CD81 protein.

• Identifying the “troublemakers” in the macrophage community: Originating from monocytes recruited to tissues after injuries, a subset of the macrophage population expressing SPP1, known as SPP1+ macrophages, have been identified as key drivers of harmful scarring in organs such as the heart, liver, lungs. These troublemaker cells bear unique markers such as the TREM2, CD9 and SPP1 genes, the last of which the Duke-NUS team had previously investigated in their quest to find a common “scar code” across fibrotic organs.

• Critical conversations between cells: Macrophages and fibroblasts, cells that produce collagen and other components to repair damaged tissue, work closely in a balanced relationship to maintain tissue health. Using single-cell technologies, researchers have found that communication between the cells is nuanced and involves a network of different signals. In fibrosis, SPP1+ macrophages, which promote scarring, increase in number and signal fibroblasts to produce scar tissue components in excess, disrupting a once-balanced relationship.

• Targeted therapeutic strategies: Deeper understanding of macrophages’ diverse nature and how they interact with the environment around them has presented potential options for treating fibrosis. Disrupting the function of proteins expressed by macrophages, such as CCL5, SPP1 and TREM2, is one tactic that can help curb scarring. Another option being studied by researchers involves inhibiting signals in non-immune cells such as fibroblasts.

Systems geneticist and co-author Professor Enrico Petretto, Director of Duke-NUS’ Center for Computational Biology, said of the potential of his team’s work: “As we continue making significant progress in fibrosis research, we wanted to create a clear and accessible resource—a ‘handbook’—to guide translational researchers globally. Our aim is to accelerate discoveries, foster new ideas and ultimately transform treatment for millions affected by fibrosis.”

With this handbook in hand, Duke-NUS researchers hope to turn today’s scientific insights into tomorrow’s life-changing therapies, bringing fresh hope to millions worldwide battling fibrosis.