Insights into muscle stem cell movement gleaned by biologists and physicists using lab-on-chip microfluidics technology

Significance 

Cell migration is the directed movement of a single cell or a group of cells in response to chemical and/or mechanical signals. This fundamental cellular process is complex and based on a multi-step physiological mechanism. To date, there is no significant molecular marker for migrating cells, so assessment of cell migration in vivo is difficult. For example, despite our extensive knowledge about muscle regeneration, the mechanisms by which myoblasts migrate during regeneration are less clear. As well, optimal muscle repair relies on stem cells and their migration within the structural and chemical microenvironment of damaged muscle. Injury activates muscle stem and satellite cells through a complex signaling cascade that involves hepatocyte growth factor (HGF), nitric oxide, Notch-Delta1 signaling and Wnt signals.

Results of the early transplantation trials that were conducted to promote muscle repair highlighted the central role of myoblast migration. The importance of cell migration has since been applied in developing cell-based disease treatments. However, it is not yet understood how myoblast migration is regulated hierarchically by chemotactic HGF or how HGF interacts with the underlying haptotactic extracellular matrix in regulating migration.

In a new study conducted by Canadian researchers at the University of Manitoba: senior PhD (Candidate) student Ziba Roveimiab and Professors Francis Lin and Judy Anderson, identified and described the interactions of haptotaxis by the composition of the extracellular matrix substrate and chemotaxis by HGF during myoblast migration. They showed that changes in the configuration of the haptotaxis substrate (from uniform to a gradient pattern going from FN to CN or vice versa) result in potent modification of myoblast chemotaxis by HGF. The research was published in the American Journal of Physiology Cell Physiology.

Using the microfluidic system pioneered by Dr. Lin’s lab, and time-lapse confocal microscopy to study cell behavior over time, the research team found that cells moving on a uniform (=) substrate of fibronectin (FN=) traveled a greater net distance, moved into the middle of a migration channel faster, and moved more as a population than those moving on uniform collagen (CN=). FN and CN substrates had different influences on cell morphology as cells traveled or extended across the channel. AS well, cells moving on FN= or FN-CN traveled further into the channel than those moving first onto CN= or CN-FN substrate.

Migration behavior was also influenced by the configuration of HGF in solution in the medium, either in a uniform concentration or a shallow or steep gradient of concentrations. On uniform FN in a steep HGF gradient or without HGF, cells only progressed to the middle of the migration channel by 10 h. By comparison, on uniform CN, migration speed at 24 h was generally slower in mid-channel and no cells reached the middle of the channel by 10 h. This finding suggested that myoblasts were “tuned” to be more sensitive to an HGF gradient and migrated slower or faster into the migration channel  at a lower concentration of HGF, when moving on uniform CN than uniform FN.

Movement of cells was prevented so cells did not reach the middle of the migration channel  at 10 h, by a substrate with an opposing-gradient pattern of CN-FN in the absence of the HGF chemotaxin. In contrast, the researchers observed an initial fast wave of cells that later slowed toward the middle of the channel at 10 h, when cells moved on the inverse opposing-gradient substrate, FN-CN (also without HGF). Finally, the speed of migration at 24 h was faster on FN-CN than CN-FN.

In summary, the team of scientists developed a research platform using the innovative capabilities of the microfluidic device system for a high-resolution study of substrate-dependent effects, including influences of both time and the HGF chemotaxin, on the speed, direction, and distance of myoblast migration. The team now aims to apply their novel findings to the fields of tissue engineering and regenerative medicine. Together with more recent research progress, the team hopes this new understanding will advance muscle-tissue engineering and help develop new treatments to promote muscle repair.

Reference

Roveimiab Z, Lin F, Anderson JE. Traction and attraction: haptotaxis substrates collagen and fibronectin interact with chemotaxis by HGF to regulate myoblast migration in a microfluidic device. Am J Physiol Cell Physiol. 2020;319(1):C75-C92.

Go To Am J Physiol Cell Physiol

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