Sca-1⁺ cardiac fibroblasts promote development of heart failure

Area of Science:

• Cardiovascular Biology
• Immunology
• Fibroblast Biology

Background:

• The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by cardiac fibroblasts in heart failure development remains unclear.
• Identifying specific fibroblast subsets and their signaling pathways is crucial for understanding cardiac pathology.

Purpose of the Study:

• To identify the pathological GM-CSF-producing cardiac fibroblast subset responsible for heart failure.
• To investigate the therapeutic potential of targeting IL-17A signaling in these specific fibroblasts.

Main Methods:

• Characterization of cardiac fibroblast subsets using cell surface markers (CD45, CD31, CD29, mEF-SK4, PDGFRα, Sca-1, periostin).
• Utilized mouse models of experimental autoimmune myocarditis and myocardial infarction.
• Employed genetic ablation of IL-17A signaling specifically in periostin-expressing cardiac fibroblasts (PostnCre Il17rafl/fl).

Main Results:

• Identified Sca-1+ periostin+ cardiac fibroblasts as the primary GM-CSF producers in cardiac inflammation models.
• Specific deletion of IL-17A signaling to these fibroblasts attenuated cardiac inflammation and protected against post-infarct heart failure and mortality.
• GM-CSF-producing Sca-1+ fibroblasts and inflammatory monocytes were reduced in treated mice; these fibroblasts were also found in human heart failure biopsies.

Conclusions:

• This study identifies a pathological GM-CSF-producing Sca-1+ cardiac fibroblast subset in human and mouse hearts with inflammatory cardiomyopathy.
• Targeting IL-17A signaling in these specific fibroblasts offers a potential therapeutic strategy for heart failure.
• Sca-1+ cardiac fibroblasts play a critical role in directing immune cell infiltration and driving heart failure progression.