Researchers hope manipulating instructor cells will lead to new regenerative and cancer therapies.

Tufts University researchers have identified what appears to be a new class of “instructor” cell they claim plays a key role in triggering melanoma-like growth in pigment cells. The team says the events leading to cancerous transformation start as a result of changes in membrane voltage in the instructor cells. This initiates a serotonin transport-based pathway that leads the progeny of stem cells to initiate abnormal growth in melanocytes. They suggest their discoveries could lead to the development of new treatments for diseases as disparate as cancer, vitiligo, and birth defects. Moreover, the future discovery of similar types of instructor cell impacting on different types of body cells could lead to new approaches to regenerative medicine as well as cancer therapy.

The Tufts University research is published in Disease Models and Mechanisms, in a paper titled, “Transmembrane voltage gradient in GlyCl-expressing cell population controls behavior in neural crest derivative in vivo.

Misregulation of stem cells is known to play a role in the development of cancers and birth defects, explains the Tufts team, led by Michael Levin, Ph.D., professor of biology and director of the Center for Regenerative and Developmental Biology. Moreover, studies have shown that stem cells exhibit unique electrophysiological profiles and that ionic currents controlled by ion-channel proteins are critical in stem cell differentiation. However, the role of bioelectrical signals still remains poorly understood, especially in vivo. To investigate the effects of membrane voltage on cell regulation further, the researchers focused on neural crest stem cells in embryos of the frog Xenopus laevis.

During development in vertebrates, including humans, neural crest cells migrate throughout the body and give rise to a range of cell types, including melanocytes and tissues in the heart, face, and skin, the team notes. Congential malformations of the neural crest are already known to lead to birth defects.

The Tufts researchers manipulated the electrical properties of a newly identified cell population found throughout the frog embryo, by using ivermectin to open the glycine gated chloride channels (GlyCl) characteristic of the newly identified cell type. They found that changing the chloride ion levels to either hyperpolarize or depolarize the cells triggered abnormal growth in distant, neural crest-derived melanocytes. The affected melanocytes proliferated abnormally and also changed shape, invading neural tissues, blood vessels, and gut in a manner typical of metastasis. When the team used different methods to manipulate the transmembrane potential of what they termed the instructor cells, the effects on distant melanocytes were the same, suggesting it was the voltage change itself and not the method used, the chloride flow, or GlyCl channel that were responsible.

Subsequent testing of human epidermal melanocytes in a depolarizing medium also resulted in a shape change similar to that found in the Xenopus tadpoles. Further investigation suggested that serotonin was the likely messenger responsible for converting the voltage change in the instructor cells to changes in the melanocytes.

“Discovering this novel bioelectric signal and new cell type could be very important in efforts to understand the mechanisms that coordinate stem cell function within the host organism and prevent tumor growth,” Dr. Levin suggests. “Ultimately it could enable us to guide cell behaviors toward regenerative medicine applications.”

The Tufts researchers are already looking at the potential for using voltage-sensitive dyes for noninvasive cancer detection, and investigating possible techniques that could prevent cancer progression through the repolarization of abnormal cells and their instructor cells.

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