Open AccessArsenic Directs Stem Cell Fate by Imparting Notch Signaling Into the Extracellular Matrix Niche
Author(s) -
Teresa Anguiano,
Amrita Sahu,
Baoli Qian,
Wan Yee Tang,
Fabrisia Ambrosio,
Aaron Barchowsky
Publication year - 2020
Publication title -
toxicological sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.352
H-Index - 183
eISSN - 1096-6080
pISSN - 1096-0929
DOI - 10.1093/toxsci/kfaa106
Subject(s) - extracellular matrix , microbiology and biotechnology , skeletal muscle , biology , notch signaling pathway , myogenesis , stem cell , myocyte , cancer research , endocrinology , signal transduction
Compromise of skeletal muscle metabolism and composition may underlie the etiology of cardiovascular and metabolic disease risk from environmental arsenic exposures. We reported that arsenic impairs muscle maintenance and regeneration by inducing maladaptive mitochondrial phenotypes in muscle stem cells (MuSC), connective tissue fibroblasts (CTF), and myofibers. We also found that arsenic imparts a dysfunctional memory in the extracellular matrix (ECM) that disrupts the MuSC niche and is sufficient to favor the expansion and differentiation of fibrogenic MuSC subpopulations. To investigate the signaling mechanisms involved in imparting a dysfunctional ECM, we isolated skeletal muscle tissue and CTF from mice exposed to 0 or 100 μg/l arsenic in their drinking water for 5 weeks. ECM elaborated by arsenic-exposed CTF decreased myogenesis and increased fibrogenic/adipogenic MuSC subpopulations and differentiation. However, treating arsenic-exposed mice with SS-31, a mitochondrially targeted peptide that repairs the respiratory chain, reversed the arsenic-promoted CTF phenotype to one that elaborated an ECM supporting normal myogenic differentiation. SS-31 treatment also reversed arsenic-induced Notch1 expression, resulting in an improved muscle regeneration after injury. We found that persistent arsenic-induced CTF Notch1 expression caused the elaboration of dysfunctional ECM with increased expression of the Notch ligand DLL4. This DLL4 in the ECM was responsible for misdirecting MuSC myogenic differentiation. These data indicate that arsenic impairs muscle maintenance and regenerative capacity by targeting CTF mitochondria and mitochondrially directed expression of dysfunctional regulators in the stem cell niche. Therapies that restore muscle cell mitochondria may effectively treat arsenic-induced skeletal muscle dysfunction and compositional decline.