Volumetric muscle loss (VML) overwhelms the innate regenerative capacity of mammalian skeletal muscle (SkM), leading to numerous disabilities and reduced quality of life. Immune cells are critical responders to muscle injury and guide tissue resident stem cell and progenitor mediated myogenic repair. However, how immune cell infiltration and inter-cellular communication networks with muscle stem cells are altered following VML and drive pathological outcomes remains underexplored. Herein, we contrast the cellular and molecular mechanisms of VML injuries that result in fibrotic degeneration or regeneration of SkM. Following degenerative VML injuries, we observe heightened infiltration of natural killer (NK) cells as well as persistence of neutrophils beyond two weeks post injury. Functional validation of NK cells revealed an antagonistic role on neutrophil accumulation in part via inducing apoptosis and CCR1 mediated chemotaxis. The persistent infiltration of neutrophils in degenerative VML injuries was found to contribute to impairments in muscle stem cell regenerative function, which was also attenuated by transforming growth factor beta 1 (TGFb1). Blocking TGFb signaling reduced neutrophil accumulation and fibrosis, as well as improved muscle specific force. Collectively, these results enhance our understanding of immune cell-stem cell crosstalk that drives regenerative dysfunction and provide further insight into possible avenues for fibrotic therapy exploration.

Forkhead box K1 (FOXK1) is a member of the FOX transcription factor family, which plays an important role in oncogenesis. However, the exact function and mechanism of FOXK1 in human colorectal cancers (CRCs) remain unclear. In the present study, we first screened for potential FOXK1 target genes by ectopically expressing FOXK1 in SW480 cells and examined the subsequent changes in the expression levels of major oncogenes using RT-PCR. We also evaluated the effects of FOXK1 regulation on growth and apoptosis. In addition, we investigated the biological impact of FOXK1 knockdown on CRC cells in vitro and in vivo. We found that FOXK1 overexpression increased the expression of multiple oncogenes in vitro. FOXK1 promoted serum-dependent and anchorage-dependent and -independent cell growth. Knockdown of FOXK1 induced G0/G1 cell cycle arrest in CRC cells. Moreover, FOXK1 suppression induced apoptosis and increased cell susceptibility to 5-fluorouracil (5-FU)-induced apoptosis. Furthermore, a xenograft model was established to explore FOXK1 shRNA-mediated tumorigenesis in vivo. A strong antitumorigenic effect of FOXK1-shRNA was enhanced when combined with 5-FU treatment. These findings implicate FOXK1 as a cell cycle and growth modulator that inhibits apoptosis in colon cancer cells. FOXK1-shRNA may serve as a novel and potent therapeutic agent, alone or with 5-FU, against colon cancer.