Small Molecule Holds Promise Against Fibrosis in Scleroderma, Other Disorders, Study Suggests

Using a new stem cell-based model, researchers have discovered a molecule that can reverse tissue damage caused by inflammation and fibrosis (scarring), a study shows.

The study, “Modeling Progressive Fibrosis with Pluripotent Stem Cells Identifies an Anti-fibrotic Small Molecule,” was published in Cell Reports.

Fibrotic diseases, including scleroderma, constitute a major global health problem due to the large number of affected individuals, the complex and unclear disease mechanism, and the variety of clinical manifestations.

Being able to replicate in a laboratory what happens to cells during fibrosis is key to better understanding these disorders. However, a preclinical model that mimics the complexity and progressive nature of fibrosis hasn’t been created yet.

“Once scarring gets out of control, we don’t have any treatments that can stop it, except for whole-organ transplant,” lead author Brigitte Gomperts, MD, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles (UCLA), said in a press release.

In the new model of fibrosis, Gomperts’ team used induced pluripotent stem cells (iPSCs), which are obtained by reprogramming blood and skin cells back into a stem cell-like state, then enabling the generation of any type of cell. The cells were differentiated into multiple cell types, which is critical for modeling fibrosis and represents a shift from prior studies of iPSCs that generated a single cell type.

“Fibrosis likely occurs as the result of interactions between multiple different cell types, so we didn’t think it made sense to use just one cell type to generate a scarring model,” said Preethi Vijayaraj, PhD, the study’s first author and a professor at UCLA’s David Geffen School of Medicine.

The cell mixture was placed on a rigid hydrogel that modeled the stiffness of a scarred organ. Cells exhibited the same behavior as if they were responding to an injury in the body, as they activated a pro-inflammatory and pro-fibrotic molecule called TGF-beta.

The model efficiently replicated the known biologic mechanisms of fibrosis, including the typical inflammatory response that initiates injury and the continued production of collagen and other components of the extracellular matrix (ECM) — which, in normal amounts, provides structural and functional support to cells. As in fibrosis, clusters of ECM-producing cells — or fibroblasts — increased in size and stiffness during the 13-day experiment.

The cells retained some form of plasticity, meaning they could change cell types, such as from an epithelial (surface) cell to a mesenchymal cell, which, in turn, can generate cartilage, bone, and fat cells. Importantly, this is the first time a fibrosis model was able to re-create plasticity, a hallmark of progressive fibrosis.

Scientists then used their model to screen about 17,000 compounds for potential anti-fibrotic effects. Over seven days, the team looked at whether these small molecules could prevent cells from acquiring a fibrotic appearance and allow them to grow as a single, non-fibrous layer of viable cells.

By targeting other molecules (agonists) that stimulate tissue repair pathways, the AA5 molecule was able to stop progressive scarring and even reverse fibrosis-associated damage in mouse models of pulmonary and ocular fibrosis, as well as in lung tissue from patients with idiopathic pulmonary fibrosis.

“This drug candidate seems to be able to stop and reverse progressive scarring in a dish by actually breaking down the scar tissue. We tested it in animal models of fibrosis of the lungs and eyes, and found that it has promise to treat both of those diseases,” Gomperts said.

“Our data suggest that approaching inflammation-driven fibrosis by targeting endogenous agonists of resolution may offer an attractive strategy to treat progressive fibrosis,” the researchers wrote in the study.