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. 2019 Jul 22;30(16):1985–1999. doi: 10.1091/mbc.E19-02-0090

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© 2019 Smith et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.

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FIGURE 1: — Myoblasts can migrate through small pores but are then less able to regenerate muscle. (A) (i) Myoblasts migrate through extracellular matrix (ECM) barriers to sites of injury to contribute to regeneration. Fibrotic ECM with small pore sizes may support calcification by resident mesenchymal stem cells. (ii) MSCs that contribute to osteogenesis navigate small pores through fibrous ECM and rigid bone. (B) Top: myoblasts and their nuclei (blue) squeeze through small constricting pores in the ECM (green). Bottom: migration through larger, more permissive matrix pores. (C) Live-cell imaging of tdTomato-expressing C2C12s that have migrated through either 3- or 8-μm pores over the course of 4–20 h. Images show migrated cells on the bottoms of nontransparent transwell pore filters. Inset scalebar = 10 μm. (D) (Left) Tibialis anterior (TA) muscles of NSG mice are injected with cardiotoxin to induce muscle damage and subsequent regeneration. After 2 d, tdTomato-expressing C2C12 myoblasts are migrated through 3- or 8-μm transwell pores for 24 h, collected postmigration, and then injected along the TA muscle (3 μm pore–migrated cells in one limb, and 8 μm pore–migrated cells in the contralateral limb). Seven days after cellular injection, muscles are dissected and fixed for histological analysis. Right images: Low- and high-magnification images of thick muscle sections showing tdTomato-expressing C2C12 cells in regenerating myofibers (white arrow) and in interstitial spaces (orange arrow). tdTomato signal is higher in muscle injected with 8 μm than 3 μm pore–migrated cells. Top scalebar = 100 μm; bottom scalebar = 20 μm. (E) The two TA muscles injected with 3 μm pore–migrated myoblasts (red points) exhibit overall fewer regenerating myofibers, as marked by centrally nucleated fibers (CNF), than the two TA muscles injected with 8 μm pore–migrated myoblasts (blue points). Each set of points, connected by a line, represents a single mouse. N = 709–1051 fibers per muscle. (F) TA muscles injected with 3 μm pore–migrated myoblasts exhibit fewer regenerating myofibers that have incorporated tdTomato-positive cells, suggesting that injected myoblasts contribute less to regeneration if they have undergone constricted migration. * indicates significant (p < 0.05) difference from 8-μm migration by a chi-squared test.