The National Institutes of Health, National Institute of Environmental Health Sciences (NIEHS), recently honored its 2016 Papers of the Year—the top 25 of 2700 publications. In that elite group, McGowan Institute for Regenerative Medicine faculty member Fabrisia Ambrosio, PhD, MPT, Director of Rehabilitation for UPMC International and an Associate Professor in the Department of Physical Medicine & Rehabilitation at the University of Pittsburgh, and her team were recognized for their paper entitled “Arsenic promotes NF-kB-mediated fibroblast dysfunction and matrix remodeling to impair muscle stem cell function,” published in the journal Stem Cells. McGowan Institute faculty member Donna Stolz, PhD, Associate Director of the Center for Biologic Imaging, University of Pittsburgh School of Medicine, and an Associate Professor in the Departments of Cell Biology and Pathology at the University of Pittsburgh, is a co-author on the study.
The paper’s abstract reads:
Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration and impaired functional recovery, relative to controls. When naïve human MuSCs were seeded onto three-dimensional decellularized muscle constructs derived from arsenic-exposed muscles, cells displayed an increased fibrogenic conversion and decreased myogenicity, compared with cells seeded onto control constructs. Consistent with myomatrix alterations, fibroblasts isolated from arsenic-exposed muscle displayed sustained expression of matrix remodeling genes, the majority of which were mediated by NF-κB. Inhibition of NF-κB during arsenic exposure preserved normal myofiber structure and functional recovery after injury, suggesting that NF-κB signaling serves as an important mechanism of action for the deleterious effects of arsenic on tissue healing. Taken together, the results from this study implicate myomatrix biophysical and/or biochemical characteristics as culprits in arsenic-induced MuSC dysfunction and impaired muscle regeneration. It is anticipated that these findings may aid in the development of strategies to prevent or revert the effects of arsenic on tissue healing and, more broadly, provide insight into the influence of the native myomatrix on stem cell behavior.
Abstract (Arsenic promotes NF-Κb-mediated fibroblast dysfunction and matrix remodeling to impair muscle stem cell function. Zhang C, Ferrari R, Beezhold K, Stearns-Reider K, D’Amore A, Haschak M, Stolz D, Robbins PD, Barchowsky A, Ambrosio F. Stem Cells; 2016 Mar;34(3):732-42.)