RESUMO
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 ß1 (TGF-ß1), 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-ß1 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-ß-rich environment favors fibrotic degeneration of the muscle during chronic injury.
Assuntos
Adipogenia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Músculo Esquelético/lesões , Doenças Musculares/tratamento farmacológico , Pirimidinas/uso terapêutico , Células-Tronco/citologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Contagem de Células , Sobrevivência Celular/efeitos dos fármacos , Doença Crônica , Colágeno/metabolismo , Venenos Elapídicos , Feminino , Fibrose , Citometria de Fluxo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Monócitos/citologia , Monócitos/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Doenças Musculares/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/deficiência , Receptores CCR2/metabolismo , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Although the regenerative potential of adult skeletal muscle is maintained by satellite cells, other stem/progenitor cell populations also reside in skeletal muscle. These heterogeneous cellular pools with mesenchymal lineage potentially play important roles in tissue homeostasis, with reciprocal collaborations between these cells and satellite cells appearing critical for effective regeneration. However, in disease settings, these mesenchymal stem/progenitors adopt a more sinister role - likely providing a major source of fibrosis, fatty tissue and extracellular matrix protein deposition in dystrophic tissue. Development of therapies for muscle degeneration therefore requires complete understanding of the multiple cell types involved and their complex interactions.