Metastatic cancer cells migrate through constricted spaces and experience significant compressive stress, but mechanisms enabling migration in confined geometries remain unclear. Cancer cell migration within confined 3-dimensional (3D) microfluidic channels has been shown to be distinct from 2D cell migration. However, whether 3D confined migration can be manipulated by mechanosensory components has not been examined in detail. In this work, we exogenously introduced a mechanosensitive channel of large conductance (MscL) into metastatic breast cancer cells MDA-MB-231. We discovered that inducing expression of a gain-of-function G22S mutant of MscL in MDA-MB-231 cells significantly reduced spontaneous lung metastasis without affecting the growth of orthotopic tumor implants. To further investigate the effects of G22S MscL on cell migration, we designed a microfluidic device with channels of various cross-sections ranging from a 2D planar environment to narrow 3D constrictions. Both MscL G22S and control breast cancer cells migrated progressively slower in more constricted environments. Migration of cells expressing MscL G22S did not differ from control cells, even though MscL was activated in cells in constricted channels of 3 μ m width. Interestingly, we found MscL expressing cells to be more frequently “stuck” at the entrance of the 3 μ m channels and failed to migrate into the microchannel. Our work demonstrates the possibility of engineering mechanotransduction for controlling confined cell migration.
In this study we evaluated if zebrafish larvae can be colonized by human gut microorganisms. We tested two strategies: (1) through transplantation of a human fecal microbiota and (2) by successively transplanting aerotolerant anaerobic microorganisms, similar to the colonization in the human intestine during early life. We used conventionally raised zebrafish larvae harboring their own aerobic microbiota to improve the colonization of anaerobic microorganisms. The results showed with the fecal transplant, that some members of the human gut microbiota were transferred to larvae. Bacillus, Roseburia, Prevotella, Oscillospira, one unclassified genus of the family Ruminococcaceae and Enterobacteriaceae were detected in 3 days post fertilization (dpf) larvae; however only Bacillus persisted to 7 dpf. Successive inoculation of Lactobacillus, Bifidobacterium and Clostridioides did not improve their colonization, compared to individual inoculation of each bacterial species. Interestingly, the sporulating bacteria Bacillus clausii and Clostridioides difficile were the most persistent microorganisms. Their endospores persisted at least 5 days after inoculating 3 dpf larvae. However, when 5 dpf larvae were inoculated, the proportion of vegetative cells in larvae increased, revealing proliferation of the inoculated bacteria and better colonization of the host. In conclusion, these results suggest that it is feasible to colonize zebrafish larvae with some human bacteria, such as C. difficile and Bacillus and open an interesting area to study interactions between these microorganisms and the host.
Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) and anterior cingulate cortex (ACC) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in both the DMS and ACC. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses, MThal-ACC synapses, and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation), but decreased subsequent morphine inhibition of transmission at MThal-ACC synapses (morphine tolerance) in a sex-specific manner; these adaptations were present in male but not female mice. Additionally, these adaptations were not observed in knockin mice expressing phosphorylation-deficient MORs, suggesting a role of MOR phosphorylation in mediating both facilitation and tolerance to morphine within this circuit. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex.
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