How Stem Cells Build Muscle Or Brain Or Bone Cells

The difference between a group of "blank" stem cells and a developing fetus is a complex series of biochemical reactions that transform stem cells into specific types of body tissue.
In this week's issue of Science, researchers at the University of Pennsylvania Medical Center report how the enzyme QSulf1 fits into this biochemical clockwork, helping cells respond to one of the many chemical signals that surround them.

"It is a problem at the heart of basic biology -- how one cell becomes muscle while an adjacent cell turns to bone," said Charles P. Emerson, PhD, Joseph P. Leidy Professor of Biology and Chair of Penn's Department of Cell and Developmental Biology. "For all we know of stem cells and the molecules involved in cell differentiation, we know very little about how these processes physically work."

As an embryo develops, different molecular signals instruct cells to produce proteins that will transform the cell into a particular tissue type, such as bone or muscle. QSulf1 functions in progenitor cells, slightly more advanced forms of stem cells that have fewer potential career paths.

According to the researchers, QSulf1 represents a new class of enzymes whose main function is to modify an important signaling co-factor called heparan sulfate proteoglycan (HSPG). It is a small yet important step in a chain of reactions involved in allowing a cell to respond to a specific molecular signal, Wnt, and transforming the cell into muscle instead of skin or bone.

"It is not enough to know what proteins are involved in embryonic development, we must understand how they work in order to eventually understand how to fix them when they fail," said Emerson.

Based on their findings, the researchers propose that Qsulf1 is released
onto the surface of specific embryonic cells where it snips off a specific sulfur-containing chemical group (called a sulfate group) that projects from a specific part of the HSPG molecule.

As a result, Wnt signaling molecules, which are bound to HSPGs on the surfaces of cells, are released, allowing Wnts to activate regulatory genes that give further career instructions.

In this study, the researchers show that QSulf1 allows embryonic cells to express a muscle master regulatory gene called MyoD, which then instructs these cells to become muscle progenitor cells instead of skin or bone progenitor cells.

These findings are not only of interest to researchers in the fields of cell biology and developmental diseases, but also highlight how much remains to be learned about the complex workings of the developing embryo.

Emerson and his colleagues first identified QSulf1 as they studied bird embryos for genes whose expression is controlled by Shh, a molecule of known importance in developmental processes. Interestingly, the QSulf1 gene remains essentially unchanged within the genomes of worms, flies, mice and humans.

"Evolution has seen fit to keep this protein around a long time," said Emerson. "What we see is the emerging picture of a fundamental player in the embryonic development of many types of organisms."

Understanding the mechanisms of stem cell specification will unlock potential new technologies for the repair of organs and tissues damaged by disease and trauma.

"If we are going to use stem cells to treat developmental disorders, there is still a great deal that basic biology must tell us," said Emerson. "We are only now beginning to understand how the body builds tissues."

Other Penn scientists who participated in the study are Marcus K.
Gustafsson; Weitao Sun; Xingbin Ai, PhD, and David M. Standiford, PhD.
Gurtej K. Dhoot, PhD, of the Royal Veterinary College, University of London, also collaborated in the research.

The research was funded by the National Institutes of Health and the Royal Society and Wellcome Trust. - By Greg Lester

[Contact: Ellen O'Brien