Adult skeletal muscle possesses remarkable regenerative capacity. This is attributed to tissue-specific stem cells, satellite cells. Interstitial stromal cells also play critical roles in muscle, and we have previously reported that Hoxa11 and Hoxd11 , expressed in the interstitial cells of muscles that attach to the zeugopod (radius and ulna), are critical for the proper patterning and development of these muscles during embryogenesis. Using a Hoxa11eGFP knock-in reporter, we show that expression continues in a subset of muscle interstitial cells through adult stages. Using Hoxa11-CreERT2 mediated lineage reporting induced at adult stages, we observe lineage initiation only in the interstitial cells of muscle, as expected. However, this Hoxa11-expressing interstitial cell lineage progressively contributes to muscle fibers at postnatal and adult stages. The contribution to these muscles at adult homeostasis significantly exceeds parallel Pax7-CreERT2 mediated lineage labeling performed in parallel. To confirm that interstitial cell nuclear contents are contributed to muscle fibers, we additionally used the nuclear specific lineage reporter, ROSA-LSL-H2BmCherry with Hoxa11-CreERT2 and observe that Hoxa11-expressing interstitial cells contribute their nuclei to myofibers. Hox lineage contribution is observed into all four muscle sub-types over months of lineage labeling. At no point after Hoxa11-mediated lineage induction do we observe lineage labeling into Pax7-expressing satellite cells. This adds to a small but growing body of evidence that supports a satellite cell-independent source of muscle tissue in vivo .

Summary Statement

Hoxa11 expression marks a novel population of muscle interstitial cells capable of extensive, satellite cell-independent contribution to skeletal muscle fibers during adult homeostasis.