Single-cell trajectories can unveil how gene regulation governs cell fate decisions. However, learning the structure of complex trajectories with two or more branches remains a challenging computational problem. We present Monocle 2, which uses reversed graph embedding to describe multiple fate decisions in a fully unsupervised manner. Applied to two studies of blood development, Monocle 2 revealed that mutations in key lineage transcription factors diverts cells to alternative fates.

Transforming growth factor-beta1 (TGF-beta1) is thought to play a crucial role in fibrotic diseases. This study demonstrates for the first time that TGF-beta1 stimulation can induce myoblasts (C2C12 cells) to express TGF-beta1 in an autocrine manner, down-regulate the expression of myogenic proteins, and initiate the production of fibrosis-related proteins in vitro. Direct injection of human recombinant TGF-beta1 into skeletal muscle in vivo stimulated myogenic cells, including myofibers, to express TGF-beta1 and induced scar tissue formation within the injected area. We also observed the local expression of this growth factor by myogenic cells, including regenerating myofibers, in injured skeletal muscle. Finally, we demonstrated that TGF-beta1 gene-transfected myoblasts (CT cells) can differentiate into myofibroblastic cells after intramuscular transplantation, but that decorin, an anti-fibrosis agent, prevents this differentiation process by blocking TGF-beta1. In summary, these findings indicate that TGF-beta1 is a major stimulator that plays a significant role in both the initiation of fibrotic cascades in skeletal muscle and the induction of myogenic cells to differentiate into myofibroblastic cells in injured muscle.

No abstract

Bacterial chemotaxis, the directed movement of cells along "chemoattractant" gradients, is among the best-characterized subjects of molecular biology 1-10. Much less is known about its physiological roles 11. Commonly, it is seen as starvation response when nutrients run out, or as escape response from harmful situations 12-16. Here, we establish an alternative role of chemotaxis by systematically examining the spatiotemporal dynamics of Escherichia coli in soft agar 12,17,18 : Chemotaxis in nutrient-replete conditions promotes the expansion of bacterial populations into unoccupied territories well before nutrients run out in the current environment. We show how low levels of chemoattractants act as aroma-like cues in this process, establishing the direction and enhancing the speed of population movement along the self-generated attractant gradients. This navigated range expansion process spreads faster and yields larger population gains than unguided expansion following the canonical Fisher-Kolmogorov dynamics 19,20 and is therefore a general strategy to promote population growth in spatially extended, nutrient-replete environments.

Nonsteroidal anti-inflammatory drugs are often prescribed after muscle injury. However, the effect of nonsteroidal anti-inflammatory drugs on muscle healing remains primarily controversial. To further examine the validity of using these drugs after muscle injury, we investigated the working mechanism of NS-398, a cyclooxygenase-2-specific inhibitor. In vitro experiments showed that NS-398 inhibited the proliferation and maturation of differentiated myogenic precursor cells, suggesting a detrimental effect on skeletal muscle healing. Using a mouse laceration model, we analyzed the in vivo effect of NS-398 on skeletal muscle healing at time points up to 4 weeks after injury. The in vivo results revealed delayed muscle regeneration at early time points after injury in the NS-398-treated mice. Compared to controls, lacerated muscles treated with NS-398 expressed higher levels of transforming growth factor-␤1, which corresponded with increased fibrosis. In addition, transforming growth factor-␤1 co-localized with myostatin, a negative regulator of skeletal muscle growth. We also found reduced neutrophil and macrophage infiltration in treated muscles, indicating that the delayed skeletal muscle healing observed after NS-398 treatment could be influenced by the anti-inflammatory effect of NS-398. Our findings suggest that the use of cyclooxygenase-2-specific inhibitors to treat skeletal muscle injuries warrants caution because they may interfere with muscle healing. Muscle injuries due to trauma, sports, or military-related circumstances occur frequently. After injury, the healing process comprises usually sequential stages that include degeneration and inflammation, muscle regeneration, and fibrosis.