Publications by authors named "Noelle D Visser"

6 Publications

  • Page 1 of 1

Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.

Bone Res 2019 Dec 10;7(1):36. Epub 2019 Dec 10.

Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.
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http://dx.doi.org/10.1038/s41413-019-0075-6DOI Listing
December 2019

Immobilization after injury alters extracellular matrix and stem cell fate.

J Clin Invest 2020 10;130(10):5444-5460

Section of Plastic Surgery, Department of Surgery.

Cells sense the extracellular environment and mechanical stimuli and translate these signals into intracellular responses through mechanotransduction, which alters cell maintenance, proliferation, and differentiation. Here we use a mouse model of trauma-induced heterotopic ossification (HO) to examine how cell-extrinsic forces impact mesenchymal progenitor cell (MPC) fate. After injury, single-cell (sc) RNA sequencing of the injury site reveals an early increase in MPC genes associated with pathways of cell adhesion and ECM-receptor interactions, and MPC trajectories to cartilage and bone. Immunostaining uncovers active mechanotransduction after injury with increased focal adhesion kinase signaling and nuclear translocation of transcriptional coactivator TAZ, inhibition of which mitigates HO. Similarly, joint immobilization decreases mechanotransductive signaling, and completely inhibits HO. Joint immobilization decreases collagen alignment and increases adipogenesis. Further, scRNA sequencing of the HO site after injury with or without immobilization identifies gene signatures in mobile MPCs correlating with osteogenesis, and signatures from immobile MPCs with adipogenesis. scATAC-seq in these same MPCs confirm that in mobile MPCs, chromatin regions around osteogenic genes are open, whereas in immobile MPCs, regions around adipogenic genes are open. Together these data suggest that joint immobilization after injury results in decreased ECM alignment, altered MPC mechanotransduction, and changes in genomic architecture favoring adipogenesis over osteogenesis, resulting in decreased formation of HO.
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http://dx.doi.org/10.1172/JCI136142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524473PMC
October 2020

Tuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis.

J Immunol 2020 04 11;204(8):2203-2215. Epub 2020 Mar 11.

Department of Surgery, University of Michigan, Ann Arbor, MI 48109;

Myeloid cells are critical to the development of fibrosis following muscle injury; however, the mechanism of their role in fibrosis formation remains unclear. In this study, we demonstrate that myeloid cell-derived TGF-β1 signaling is increased in a profibrotic ischemia reperfusion and cardiotoxin muscle injury model. We found that myeloid-specific deletion of abrogates the fibrotic response in this injury model and reduces fibro/adipogenic progenitor cell proliferation while simultaneously enhancing muscle regeneration, which is abrogated by adaptive transfer of normal macrophages. Similarly, a murine TGFBRII-Fc ligand trap administered after injury significantly reduced muscle fibrosis and improved muscle regeneration. This study ultimately demonstrates that infiltrating myeloid cell TGF-β1 is responsible for the development of traumatic muscle fibrosis, and its blockade offers a promising therapeutic target for preventing muscle fibrosis after ischemic injury.
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http://dx.doi.org/10.4049/jimmunol.1900814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080967PMC
April 2020

Regulation of heterotopic ossification by monocytes in a mouse model of aberrant wound healing.

Nat Commun 2020 02 5;11(1):722. Epub 2020 Feb 5.

Section of Plastic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA.

Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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http://dx.doi.org/10.1038/s41467-019-14172-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002453PMC
February 2020

Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.

Bone Res 2019 10;7:36. Epub 2019 Dec 10.

1Department of Surgery, University of Michigan, Ann Arbor, MI 48109 USA.

Heterotopic ossification (HO) is a debilitating condition characterized by the pathologic formation of ectopic bone. HO occurs commonly following orthopedic surgeries, burns, and neurologic injuries. While surgical excision may provide palliation, the procedure is often burdened with significant intra-operative blood loss due to a more robust contribution of blood supply to the pathologic bone than to native bone. Based on these clinical observations, we set out to examine the role of vascular signaling in HO. Vascular endothelial growth factor A (VEGFA) has previously been shown to be a crucial pro-angiogenic and pro-osteogenic cue during normal bone development and homeostasis. Our findings, using a validated mouse model of HO, demonstrate that HO lesions are highly vascular, and that VEGFA is critical to ectopic bone formation, despite lacking a contribution of endothelial cells within the developing anlagen.
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http://dx.doi.org/10.1038/s41413-019-0075-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904752PMC
December 2019

Plant Host and Geographic Location Drive Endophyte Community Composition in the Face of Perturbation.

Microb Ecol 2016 10 24;72(3):621-32. Epub 2016 Jun 24.

Evolution, Ecology and Behavior Program, Department of Biology, Indiana University, 1001 E. 3rd St., Bloomington, IN, 47405, USA.

All plants form symbioses with endophytic fungi, which affect host plant health and function. Most endophytic fungi are horizontally transmitted, and consequently, local environment and geographic location greatly influence endophyte community composition. Growing evidence also suggests that identity of the plant host (e.g., species, genotype) can be important in shaping endophyte communities. However, little is known about how disturbances to plants affect their fungal symbiont communities. The goal of this study was to test if disturbances, from both natural and anthropogenic sources, can alter endophyte communities independent of geographic location or plant host identity. Using the plant species white snakeroot (Ageratina altissima; Asteraceae), we conducted two experiments that tested the effect of perturbation on endophyte communities. First, we examined endophyte response to leaf mining insect activity, a natural perturbation, in three replicate populations. Second, for one population, we applied fungicide to plant leaves to test endophyte community response to an anthropogenic perturbation. Using culture-based methods and Sanger sequencing of fungal isolates, we then examined abundance, diversity, and community structure of endophytic fungi in leaves subjected to perturbations by leaf mining and fungicide application. Our results show that plant host individual and geographic location are the major determinants of endophyte community composition even in the face of perturbations. Unexpectedly, we found that leaf mining did not impact endophyte communities in white snakeroot, but fungicide treatment resulted in small but significant changes in endophyte community structure. Together, our results suggest that endophyte communities are highly resistant to biotic and anthropogenic disturbances.
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http://dx.doi.org/10.1007/s00248-016-0804-yDOI Listing
October 2016