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Immune cells gobble out-of-control fibroblasts when “don’t-eat-me” signal is blocked

Idiopathic pulmonary fibrosis, scleroderma and liver cirrhosis are just a few of a pantheon of confusingly named, difficult-to-treat and sometimes life-threatening diseases caused by the malfunction of a single cell type. But until now it's not been clear whether the disorders shared a deeper root cause.

Now Stanford pathologist Gerlinde Wernig, MD, and stem cell biologist Irving Weissman, MD, have identified a cell signaling pathway that, when mutated, causes widespread fibrosis in laboratory mice. What's more, they showed that an antibody currently in trials as an anti-cancer treatment can reverse the condition. They published their results this week in the Proceedings of the National Academies of Science.

From our release:

Fibrosis occurs when the body’s normal response to injury goes astray. An overenthusiastic or inappropriately timed proliferation of cells called fibroblasts, which make up the connective tissue surrounding and supporting all of our organs, can lead to many devastating diseases. Until now, it’s not been clear whether these diseases share a common biological pathway.

Wernig and Weissman, who directs Stanford's Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine, found that human fibrotic tissue expresses high levels of a key signaling protein called c-Jun. When Wernig genetically engineered mice to overexpress c-Jun, the animals developed fibrosis in nearly every organ of their bodies. She also noticed that, in many cases, these overactive fibroblasts were surrounded by immune cells called macrophages. She knew from previous work in Weissman's lab that human tumors express a "don't-eat-me" signal on their surface to protect them from macrophages. She and Weissman wondered if something similar was happening in fibrosis.

More from our release:

'Like in cancer, these fibroblasts are proliferating excessively beyond what should be their natural limit,' Weissman said. 'We therefore wondered whether they are also expressing the ‘don’t eat me’ signal on their surfaces to protect them from the immune system.'

When Wernig treated mice with c-Jun-induced lung fibrosis with daily injections of anti-CD47 antibody, the animals exhibited significantly better lung function, lived longer than their peers and cleared the fibrosis.

Recently the anti-CD47 antibody has been shown to prevent or reverse the development of atherosclerotic plaques in strains of laboratory mice predisposed to develop cardiovascular disease. The researchers are now eager to learn whether it may also help derail or reverse fibrosis.

Previously: Cancer uses inflammatory pathways to protect itself, Double agent: Anti-tumor drug already in human trials may combat atherosclerosis, Single antibody shrinks or eliminates human tumors in mice at Stanford

 

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