[Show abstract][Hide abstract] ABSTRACT: 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.
Nature medicine 06/2015; 21(7). DOI:10.1038/nm.3869 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Skeletal muscle (SM) damage triggers a stage of transient extracellular matrix deposition that must end promptly to avoid permanent fibrosis. Here we studied the interaction between monocyte/macrophages and multipotent mesenchymal cells during SM regeneration. In wild type (WT) mice, acute muscle damage induces the proliferation and expansion of a population of pro-myogenic multipotent mesenchymal cells named Fibro/Adipogenic Progenitors (FAPs) between post-damage day 1 (D1) and D4. Contraction of the FAP population is observed between D5 and D7 during which the population returns to pre-damage levels. As these cells are the progenitors of fibrogenic myofibroblasts, such clearance is critical to avoid fibrotic tissue degeneration. We determined that their contraction is due to death by apoptosis. Importantly, FAP clearance is inefficient in CCR2KO mice in which infiltration by bone marrow-derived monocytes is impaired. We found that TNFα, a cytokine largely produced by proinflammatory macrophages, induces FAP apoptosis in vitro. Systemic blockade of TNFα in WT mice during SM regeneration leads to increased FAP survival, their differentiation in collage-producing cells and deposition of fibrotic matrix in the interstitial space amongst muscle fibers. Interestingly we found that TGFβ, a profibrogenic cytokine that is secreted by anti-inflammatory macrophages during the well-characterized proinflammatory-to-anti-inflammatory phenotype switch, is capable of blocking TNFα-mediated apoptosis induction both in vitro and in vivo. We found that as TNFα production declines production of TGFβ increases, suggesting that in the absence of TNFα the persisting FAPs are exposed to a profibrotic environment. Indeed blockade of TGFb signaling leads to a decrease in the number of FAPs both in the WT and CCR2-/- TA. Altogether our data indicate that innate immune cells modulate fibrosis by regulating the FAP population via TNFα and TGFβ signaling. Our work reveals new mechanisms underlying the observation that inflammatory cells are critical for efficient regeneration.
Keystone Symposia. Fibrosis: From Bench to Bedside, Keystone, Colorado; 03/2014
[Show abstract][Hide abstract] ABSTRACT: 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 linage potential 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 extra cellular 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. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Adult stem cells are activated to proliferate and differentiate during normal tissue homeostasis as well as in disease states and injury. This activation is a vital component in the restoration of function to damaged tissue via either complete or partial regeneration. When regeneration does not fully occur, reparative processes involving an overproduction of stromal components ensure the continuity of tissue at the expense of its normal structure and function, resulting in a "reparative disorder". Adult stem cells from multiple organs have been identified as being involved in this process and their role in tissue repair is being investigated. Evidence for the participation of mesenchymal stromal cells (MSCs) in the tissue repair process across multiple tissues is overwhelming and their role in reparative disorders is clearly demonstrated, as is the involvement of a number of specific signaling pathways. Transforming growth factor beta, bone morphogenic protein and Wnt pathways interact to form a complex signaling network that is critical in regulating the fate choices of both stromal and tissue-specific resident stem cells (TSCs), determining whether functional regeneration or the formation of scar tissue follows an injury. A growing understanding of both TSCs, MSCs and the complex cascade of signals regulating both cell populations have, therefore, emerged as potential therapeutic targets to treat reparative disorders. This review focuses on recent advances on the role of these cells in skeletal muscle, heart and lung tissues.
[Show abstract][Hide abstract] ABSTRACT: The intestinal messenger RNA expression signature is affected by the presence and composition of the endogenous microbiota, with effects on host physiology. The intestine is also characterized by a distinctive micronome. However, it is not known if microbes also impact intestinal gene expression epigenetically. We investigated if the murine caecal microRNA expression signature depends on the presence of the microbiota, and the potential implications of this interaction on intestinal barrier function. Three hundred and thirty four microRNAs were detectable in the caecum of germ-free and conventional male mice and 16 were differentially expressed, with samples from the two groups clustering separately based on their expression patterns. Through a combination of computational and gene expression analyses, including the use of our curated list of 527 genes involved in intestinal barrier regulation, 2,755 putative targets of modulated microRNAs were identified, including 34 intestinal barrier-related genes encoding for junctional and mucus layer proteins and involved in immune regulation. This study shows that the endogenous microbiota influences the caecal microRNA expression signature, suggesting that microRNA modulation is another mechanism through which commensal bacteria impact the regulation of the barrier function and intestinal homeostasis. Through microRNAs, the gut microbiota may impinge a much larger number of genes than expected, particularly in diseases where its composition is altered. In this perspective, abnormally expressed microRNAs could be considered as novel therapeutic targets.
International journal of biological sciences 01/2012; 8(2):171-86. DOI:10.7150/ijbs.8.171 · 4.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although classical dogma dictates that satellite cells are the primary cell type involved in skeletal muscle regeneration, alternative cell types such as a variety of inflammatory and stromal cells are also actively involved in this process. A model describing myogenic cells as direct contributors to regeneration and nonmyogenic cells from other developmental sources as important accessories has emerged, with similar systems having been described in numerous other tissues in the body. Increasing evidence supports the notion that inflammatory cells function as supportive accessory cells, and are not merely involved in clearing damage following skeletal muscle injury. Additionally, recent studies have highlighted the role of tissue resident mesenchymal cell populations as playing a central role in regulating regeneration. These "accessory" cell populations are proposed to influence myogenesis via direct cell contact and secretion of paracrine trophic factors. The basic foundations of accessory cell understanding should be recognized as a crucial component to all prospects of regenerative medicine, and this chapter intends to provide a comprehensive background on the current literature describing immune and tissue-resident mesenchymal cells' role in skeletal muscle regeneration.
Current Topics in Developmental Biology 01/2011; 96:139-65. DOI:10.1016/B978-0-12-385940-2.00006-1 · 4.68 Impact Factor