Alisa Mueller

All Publications

• Fibroblasts in immune responses, inflammatory diseases and therapeutic implications. Nature reviews. Rheumatology Zou, A. E., Kongthong, S., Mueller, A. A., Brenner, M. B. 2025

  Abstract

  Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.

  View details for DOI 10.1038/s41584-025-01259-0

  View details for PubMedID 40369134

  View details for PubMedCentralID 393721

• Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nature communications Du, H. n., Shih, C. H., Wosczyna, M. N., Mueller, A. A., Cho, J. n., Aggarwal, A. n., Rando, T. A., Feldman, B. J. 2017; 8 (1): 669

  Abstract

  Coordinated activation of muscle stem cells (known as satellite cells) is critical for postnatal muscle growth and regeneration. The muscle stem cell niche is central for regulating the activation state of satellite cells, but the specific extracellular signals that coordinate this regulation are poorly understood. Here we show that macrophages at sites of muscle injury induce activation of satellite cells via expression of Adamts1. Overexpression of Adamts1 in macrophages in vivo is sufficient to increase satellite cell activation and improve muscle regeneration in young mice. We demonstrate that NOTCH1 is a target of ADAMTS1 metalloproteinase activity, which reduces Notch signaling, leading to increased satellite cell activation. These results identify Adamts1 as a potent extracellular regulator of satellite cell activation and have significant implications for understanding the regulation of satellite cell activity and regeneration after muscle injury.Satellite cells are crucial for growth and regeneration of skeletal muscle. Here the authors show that in response to muscle injury, macrophages secrete Adamts1, which induces satellite cell activation by modulating Notch1 signaling.

  View details for PubMedID 28939843

• Intronic polyadenylation of PDGFR alpha in resident stem cells attenuates muscle fibrosis NATURE Mueller, A. A., van Velthoven, C. T., Fukumoto, K. D., Cheung, T. H., Rando, T. A. 2016; 540 (7632): 276-?

  Abstract

  Platelet-derived growth factor receptor α (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signalling through this receptor promotes muscle development in growing embryos and angiogenesis in regenerating adult muscle. However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis. This excessive collagen deposition, which is seen in aged and diseased muscle, interferes with muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders. Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show in mice that PDGFRα signalling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. We found that FAPs produce multiple transcriptional variants of Pdgfra with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signalling and to prevent FAP over-activation. Moreover, increasing the expression of this isoform limits fibrosis in vivo in mice, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem-cell populations.

  View details for DOI 10.1038/nature20160

  View details for Web of Science ID 000389548700058

  View details for PubMedID 27894125

  View details for PubMedCentralID PMC5384334

• Type 2 Innate Signals Stimulate Fibro/Adipogenic Progenitors to Facilitate Muscle Regeneration CELL Heredia, J. E., Mukundan, L., Chen, F. M., Mueller, A. A., Deo, R. C., Locksley, R. M., Rando, T. A., Chawla, A. 2013; 153 (2): 376-388

  Abstract

  In vertebrates, activation of innate immunity is an early response to injury, implicating it in the regenerative process. However, the mechanisms by which innate signals might regulate stem cell functionality are unknown. Here, we demonstrate that type 2 innate immunity is required for regeneration of skeletal muscle after injury. Muscle damage results in rapid recruitment of eosinophils, which secrete IL-4 to activate the regenerative actions of muscle resident fibro/adipocyte progenitors (FAPs). In FAPs, IL-4/IL-13 signaling serves as a key switch to control their fate and functions. Activation of IL-4/IL-13 signaling promotes proliferation of FAPs to support myogenesis while inhibiting their differentiation into adipocytes. Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues.

  View details for DOI 10.1016/j.cell.2013.02.053

  View details for Web of Science ID 000317349700016

  View details for PubMedID 23582327

  View details for PubMedCentralID PMC3663598

• All's well that ends well: alternative polyadenylation and its implications for stem cell biology CURRENT OPINION IN CELL BIOLOGY Mueller, A. A., Cheung, T. H., Rando, T. A. 2013; 25 (2): 222-232

  Abstract

  Stem cell quiescence, activation, and differentiation are governed by a complex network of molecular pathways. There has been a growing recognition that posttranscriptional modifications, such as alternative polyadenylation (APA) of transcripts, play an important role in regulating gene expression and function. Recent analyses of stem cell populations have suggested that APA controls stem cell fate and behavior. Here, we review recent developments that have shaped our understanding of the control of stem cell behavior by APA and we highlight promising areas for future investigation.

  View details for DOI 10.1016/j.ceb.2012.12.008

  View details for Web of Science ID 000317886100012

  View details for PubMedID 23357469

  View details for PubMedCentralID PMC3615088