Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β-rich environment favors fibrotic degeneration of the muscle during chronic injury.

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Acute skeletal muscle injury triggers an expansion of fibro/adipogenic progenitors (FAPs) and a transient stage of fibrogenesis characterized by extracellular matrix deposition. While the perpetuation of such phase can lead to permanent tissue scarring, the consequences of its suppression remain to be studied. Using a model of acute muscle damage we were able to determine that pharmacological inhibition of FAP expansion by Nilotinib, a tyrosine kinase inhibitor with potent antifibrotic activity, exerts a detrimental effect on myogenesis during regeneration. We found that Nilotinib inhibits the damage-induced expansion of satellite cells in vivo, but it does not affect in vitro proliferation, suggesting a non cell-autonomous effect. Nilotinib impairs regenerative fibrogenesis by preventing the injury-triggered expansion and differentiation of resident CD45(-):CD31(-):α7integrin(-):Sca1(+) mesenchymal FAPs. Our data support the notion that the expansion of FAPs and transient fibrogenesis observed during regeneration play an important trophic role toward tissue-specific stem cells.

The cardiac stroma contains multipotent mesenchymal progenitors. However, lineage relationships within cardiac stromal cells are still poorly understood. Here, we identify heartresident PDGFRa + Sca-1 + cells as cardiac Fibro/Adipogenic Progenitors (cFAPs) and show that they respond to ischemic damage by generating fibrogenic cells. Pharmacological blockade of this differentiation step with an anti-fibrotic tyrosine kinase inhibitor decreases post-myocardial infarction (MI) remodeling and leads to improvements in heart function. In the undamaged heart, activation of cFAPs through lineage-specific deletion of the quiescence factor Hic1 reveals additional pathogenic potential, causing fibro-fatty infiltration of the myocardium and driving major pathological features of Arrhythmogenic Cardiomyopathy (AC). Highlights• A subpopulation of PDGFRa + , Sca-1 + cells, previously considered to be a sub-type of cardiac fibroblasts, are multipotent mesenchymal progenitors,• Cardiac damage triggers the differentiation of PDGFRa + Sca-1 + cells into Sca-1cells expressing a fibrogenic transcriptional programme,• Blockade of the cFAP-to-fibroblast transition by Nilotinib ameliorated cardiac dysfunction post-MI and modulated cardiac remodelling.• Studies performed on a model of experimentally-induced AC confirmed that cFAPs are a source of both cardiac fibroblasts and adipocytes in vivo.• Conversely, in the undamaged heart, activation of cFAPs by means of lineage-specific deletion of transcription factor Hic1, resulted in fibro/fatty cardiac degeneration and pathological alterations reminiscent of AC. Collectively, our findings show that a proportion of what are commonly termed "fibroblasts" are actually multipotent .