The human heart and brain seem to have very little in common, structurally, functionally, or even metaphorically (after all, when faced with a decision, we say you’re either guided by reason or following your emotions). However, these two incredibly complex organs share at least one trait: the cells responsible for everyday functioning have high degrees of electrical excitability.
In the brain, neurons use electrical activity to coordinate and send information throughout the nervous system. Meanwhile, in the heart, cardiomyocytes (heart muscle cells), use electrical signaling to coordinate the contractions that pump life-sustaining blood. Importantly, calcium plays a crucial role in the electrical functioning of both organs.
While cells in other parts of the body use electrical signals to send messages or trigger actions, this phenomenon is particularly associated with the heart and brain. This commonality is the basis for an ongoing collaboration between two research labs affiliated with the UW for Stem Cell and Regenerative Medicine (ISCRM).
Recently, in an exciting advance for the field, this partnership produced a cell line capable of measuring electrical activity in the heart and brain with greater speed and accuracy.
The new cell line is described in a paper appearing in the journal Stem Cell Research. The senior author of the study is Dr. Silvia Marchiano, a cardiovascular scientist and an Acting Instructor in the Department of Lab Medicine and Pathology. Her co-author is Dr. Andy Williams, an Acting Instructor in the lab of ISCRM faculty member Jessica Young. The first author of the paper is Noah Bowers, an undergraduate research fellow in the Marchiano Lab. ISCRM faculty member Nate Sniadecki is also an author.
“If we’re talking about investigating electrical activity, there is significant overlap between the heart and the brain,” says Williams. “And tracking this activity has become easier with the use of tools like optical sensors, which measure changes in calcium levels, and with the use of stem cells, which make it possible to create human neurons and cardiomyocytes to study in the lab.”
The team set out to determine whether the two tools could be combined to create a new way for scientists to gain insights into how these organs work and what causes problems to arise.
In the investigation, the researchers genetically engineered a widely used stem cell line to carry a highly sensitive calcium sensor called GCaMP8f – like installing new software on a computer that has the ability to self-replicate. The sensor glowed green when calcium levels rose inside cells, allowing the team to observe cellular activity in real-time under a microscope: proof of concept that embedding the sensor inside stem cells works.
Much of the validation and characterization of the newly engineered stem cell line was performed by Noah Bowers, who first gained experience working with GCaMP technology as an ISCRM Undergraduate Fellow. In this study, Bowers teamed up with Likitha Nimmagaada, a PhD student in the lab of ISCRM Director Jen Davis and Dr. Ariana Frey, who recently completed her PhD in the lab of ISCRM faculty member Ying Zheng. The trainees worked together to confirm that the sensor had been correctly integrated into the stem cell genome and conducted calcium imaging experiments in stem cell-derived cardiomyocytes to demonstrate that the reporter accurately tracked the rapid calcium signals associated with heart cell activity. These efforts helped establish the reliability of this new platform for studying the function of electrically active cells such as cardiomyocytes and neurons.
Marchiano speaks to the value of the genetically-engineered stem cell line for her research in heart regeneration. “Two of the critical factors we look at when we study the heart are electrical activity and contractile force. It’s traditionally very challenging to measure both at the same time. This makes it easier, especially in 3D engineered heart tissues, where we can now achieve a more even distribution of the response because the sensors are embedded in the genome.”
She adds that two labs at other universities have already asked to use the new stem cell line, an indication of its usefulness for researchers studying early human development, disease pathology, drug responses, and the therapeutic potential of cell-based therapies.
Williams echoes the usefulness of the stem cell line for brain research in the Young Lab, where they have seen that neurons with a mutation associated with Alzheimer’s disease are more electrically active than healthy cells.
“This tool opens up the possibility of more complex modeling,” says Williams. “One reason is that we are measuring activity by light, which is a much less invasive approach than other methods. We can get more detailed observations from brain organoids, for example, without having to destroy the tissue we’re studying.”