Discovery of signaling pathways could lead to faster, more reliable human stem cell differentiation

A recent discovery has opened a possible avenue to improve human health by better understanding how to engineer human stem cell differentiation.

Texas A&M University chemical engineering professor Dr. Gregory Reeves led this discovery of the highly conserved bone morphogenetic protein (BMP) signaling pathway, which functions in all animals and can achieve diverse outcomes in depending on the context.

“With this research, we are beginning to develop a road map for how to modify cells, such as adult human stem cells,” Reeves said. “They differentiate more quickly and reliably, which would enable advancements in the therapeutic potential of stem cells.”

Reeves and his team observed how cellular signaling pathways determine cellular decision-making in different tissues and contexts. Signaling pathways such as the BMP pathway play an important role in these cellular responses.

“A cell is definitely a complex system,” Reeves said. “So it’s not surprising that we find engineering principles in the cell. I think as we study biology, we find that biological systems are full of engineering principles, and I’m very interested by studying how these engineering principles are there.”

This cell signaling pathway is explored in more detail in Reeves’ recently published article in the journal Biology and applications of npj systems.

The article examines how the BMP pathway balances tradeoffs between three system-level behaviors, or performance objectives (POs): speed, noise suppression, and the ability to act as a linear sensor.

“In fly embryos, when the signaling pathway becomes active, it responds very quickly, but if you look at the same signaling pathway in other scenarios, like in human stem cells, it takes a lot longer, but that could give it more ability to filter out noise,” Reeves said. “The question we are studying is how the same pathway, with the same molecules, reacts differently.”

The team’s findings reveal that varying the concentration of BMP signaling proteins inside the cell allows the pathway to achieve a diverse PO balance.

However, because the BMP pathway is used repeatedly throughout the life cycle of all animals, its behavior at the systemic level varies from context to context, even though the connectivity of the pathway remains almost constant.

“Different systems require different tradeoffs that they emphasize,” Reeves said. “Even though the pathway is the same in all cells, the concentrations of signaling proteins are different from cell to cell. So in the fly embryo you might have high levels of signaling proteins, this which is a fast system; and in the human cell, you could have low levels which would make the system slower, but it would be less noisy.

Research has shown that due to competition among POs, the pathway cannot simultaneously optimize all three, but must make trade-offs between POs.

Armed with this knowledge, the team applied multi-objective optimization to identify optimal trade-offs between diverse requirements and found that the BMP pathway effectively balances competing OPs across species.

“We can modify it to be a little faster, a little less noisy, and we will sacrifice the qualities of the linear sensor,” Reeves said.