Redistribution of the chromatin remodeler Brg1 directs smooth muscle-derived adventitial progenitor-to-myofibroblast differentiation and vascular fibrosis.

Vascular smooth muscle-derived Sca1+ adventitial progenitor (AdvSca1-SM) cells are tissue-resident, multipotent stem cells that contribute to progression of vascular remodeling and fibrosis. Upon acute vascular injury, AdvSca1-SM cells differentiate into myofibroblasts and are embedded in perivascular collagen and the extracellular matrix. While the phenotypic properties of AdvSca1-SM-derived myofibroblasts have been defined, the underlying epigenetic regulators driving the AdvSca1-SM-to-myofibroblast transition are unclear. We show that the chromatin remodeler Smarca4/Brg1 facilitates AdvSca1-SM myofibroblast differentiation. Brg1 mRNA and protein were upregulated in AdvSca1-SM cells after acute vascular injury, and pharmacological inhibition of Brg1 by the small molecule PFI-3 attenuated perivascular fibrosis and adventitial expansion. TGF-ß1 stimulation of AdvSca1-SM cells in vitro reduced expression of stemness genes while inducing expression of myofibroblast genes that was associated with enhanced contractility; PFI blocked TGF-ß1-induced phenotypic transition. Similarly, genetic knockdown of Brg1 in vivo reduced adventitial remodeling and fibrosis and reversed AdvSca1-SM-to-myofibroblast transition in vitro. Mechanistically, TGF-ß1 promoted redistribution of Brg1 from distal intergenic sites of stemness genes and recruitment to promoter regions of myofibroblast-related genes, which was blocked by PFI-3. These data provide insight into epigenetic regulation of resident vascular progenitor cell differentiation and support that manipulating the AdvSca1-SM phenotype will provide antifibrotic clinical benefits.

Video corroboration of player incurred impacts using trunk worn sensors among national ice-hockey team members.

PURPOSE: Video corroboration of player incurred impacts (PII) using trunk-worn wearable sensors (WS) among national ice-hockey team members. METHODS: 23 members of the U.S. National (NTDP) U18 team consented to procedures approved by EMU Human Subjects Committee. Bioharness-3 (Zephyr, MD) WS recorded occurrences of PII during games and impacts were generated using Impact Processor (Zephyr, MD). Eight players with the top activity levels each game determined by WS, were observed using video and synchronized with game video collected by NTDP staff. Impacts identified by WS of 6-7.9 g (Z3), 8-9.9 g (Z4) and 10+ g (Z5) were used to corroborate PII. Magnitude and duration of each identified impact were compared by category using MANOVA with Tukey post hoc (α = 0.05; SPSS 22.0, IBM, NY). RESULTS: Of 419 on-ice impacts, 358 were confirmed true PII (85.5%), 60 as other non-PII (14.3%) and 1 false positive (0.2%). For 358 PII, 17 (4.1%) were 1) Board contact/no check, 74 (17.7%), 2) Board contact/check, 202 (48.2%), 3) Open ice check, 65 (15.5%), 4) Player fall. Of 60 Non-PII, 19 (4.5%) as 5) other form of player to player event, 16 (3.8%) as 6) Hard Stop, 19 (4.5%) as 7) Slapshots and 6 (1.4%) as 8) other identifiable player events. 160 of the 200 Z3 events were PII (80%), 103 of 110 Z4 events (93.6%) and 95 of 109 Z5 events were PII (87.2%). The magnitude of impacts was not different by category, but the duration of category 6 (Hard stop; .058 s) was lower than categories 2, 4 and 7 (.112, .112, .133 s, respectively, p < .05). CONCLUSION: These data show that using some limited criteria (e.g. impact magnitude and duration), PII can be identified with relatively high accuracy in ice hockey using trunk-worn wearable sensors.