Lab-grown skin captures the complexities of real disease to develop more effective treatments for scleroderma and other life-threatening conditions

For the 300,000 Americans living with the immune disease scleroderma, better treatments can’t come soon enough. The rare and sometimes fatal illness stiffens and scars tissue in organs like the lungs, liver, and kidneys, as well as skin. It may quietly affect one patch of skin for years or rapidly turn life-threatening, depending on where and how severely it strikes.

Traditional lab and animal studies cannot reflect scleroderma’s complexity. But now researchers from Tufts University and Geisel School of Medicine at Dartmouth have developed a new 3D tissue model, which gives researchers a better tool to understand what drives tissue cells to go haywire in the scarring process, which is called fibrosis. The new model might also lead to better predictions for which treatments could help patients.

Using skin and blood samples from scleroderma patients, the team grew lab-based skin: pinkish, pancake-like, little disks of tissue that more fully replicate how the disease develops in the body. “Under the microscope, you can’t tell the key features in our lab-grown skin apart from actual skin,” says Jonathan Garlick, a professor of basic and clinical translational sciences at Tufts University School of Dental Medicine and the study’s senior author.

“By mimicking real tissue and how scleroderma progresses differently in different people, the 3D tissue model can help scientists develop better, more personalized treatments. We also believe it can be adapted for research into all diseases that cause fibrosis,” such as myocardial fibrosis and pulmonary fibrosis, he says.

Published recently in Tissue Engineering: Part C: Methods, the model is the first to include two key immune cells—T cells and macrophages—alongside patient-derived skin and connective tissue cells. “That makes this model especially powerful, as these immune cells are what drive the body to produce excessive amounts of collagen that cause tissue to lose the ability to function normally,” says Garlick.

The 3D tissue model also preserves the natural diversity of cells that shapes disease but often is not captured in traditional lab models.

“When we take cells from a patient and put them onto a two-dimensional plastic dish to study a disease, that almost immediately biases those cells to start growing in a very homogenous way,” says Garlick. “But in the body, cells grow within complex tissues, where diverse cell types and the tissue environment shape how they behave.”

The 3D model looks and functions like actual tissue, he says. “And when we look at the whole population of cells in a true tissue context, we preserve more complex cell types in ways that are very different from cells growing flat on plastic.”

The new model allows scientists to isolate individual single cells from the tissue and look at which genes are turned on or off. “By pinpointing which genes are active in each individual cell, we can better understand what drives disease and help determine more quickly which patients may benefit from which therapies, whether that’s someone whose fibrosis is causing scarring in multiple organs or a person with just a localized patch of thicker skin,” says Garlick.

Garlick and his co-investigators know too well that there is no time to lose. They work closely with individuals with scleroderma through their patient support groups to ensure that their bench research reflects the experiences and priorities of those living with the disease.

Ultimately, the research team hopes the 3D tissues will provide a far more predictive way to test the safety and efficacy of high-potential new drugs, filling a critical research gap in speeding therapies from bench to bedside.

“Some scleroderma patients we have strong connections with end up getting stem cell transplants. Some get lung transplants,” Garlick says. “And every year when we attend Scleroderma Foundation fundraising walks, we see pictures and memorials for people we’ve known in the community who lost their lives too soon to this terrible disease.”

Isha Singh from Tufts University School of Dental Medicine is the first author. Research reported in this article was supported by the National Institutes of Health’s National Center for Advancing Translational Sciences under award number UM1TR004398, as well as a grant from the National Scleroderma Foundation. Complete information on authors, funders, methodology, limitations, and conflicts of interest is available in the published paper.  The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.