Stem cells grown in lab mirror normal developmental steps

Jun 20 2005

Johns Hopkins scientists have developed a way to study the earliest steps of human blood development using human embryonic stem cells grown in a lab dish instead of the embryos themselves.

The process avoids some of the ethical and technical obstacles involved in such research, according to the Johns Hopkins investigators.

The Johns Hopkins researchers' system involves the study of existing embryonic stem cell lines derived from in vitro fertilization methods, and so doesn't require generation of embryos through cloning, a technique recently reported by South Korean scientists.

In their report on the work in the June issue of the journal Blood, the Johns Hopkins team demonstrated a clear similarity between how human embryonic stem cells specialize into blood cells and how blood cells develop in human embryos.

"Our findings provide an unparalleled opportunity to study the basic questions of human development, like 'Where does blood come from?'" says Elias Zambidis, M.D., Ph.D., first author on the paper and an assistant professor of pediatrics and oncology in the Johns Hopkins School of Medicine.

Knowing the steps by which stem cells develop into blood cells are likely to help medical researchers figure out how to treat cancers of the blood, such as leukemia and lymphoma, Zambidis notes.

"More and more we're learning that the genes that turn on in the embryo to make blood stem cells are the same genes that go wrong in cancer," he says. "So if we understand what the important genes are and how they work, we might be able to develop and to target new cancer therapies more effectively."

Historically, scientists have worked on mouse and zebrafish models of embryological blood cell development, but ethical and technical barriers have stood in the way of an in-depth study of blood formation in human embryos. In the new work, Hopkins scientists and colleagues from the University of Pittsburgh School of Medicine used laboratory-grown dishes of human stem cells, in clumps called human embryoid bodies, and observed three distinct steps taken by stem cells on their way to becoming blood cells.

Without any chemical manipulation or stimulation, the clusters of human stem cells first became colonies of cells that can produce endothelium, or the tissue that makes up the circulatory system. These colonies can then also form the precursors of blood cells, in a structure similar to the yolk sac of human embryos. Finally, some of the cells in the colonies form blood cells similar to those found in the liver and bone marrow of a developing fetus, making it simple for the researchers to pick out the blood cells for further investigation. "We were quite surprised to find that these steps proceeded spontaneously, without the need for stimulation by growth factors or other chemicals," says Zambidis. "It's likely that the same method of picking out certain kinds of cells could be used to study processes other than blood cell development."

Most importantly, Zambidis says, the stages of blood cell development he and his team found in the stem cell lines correlate with what is already known about early stages of human blood cell development in embryos in the womb. "We've captured these phases of stem cell specialization, or differentiation, in a dish," says Zambidis. "Now we can study these phases and hopefully help solve the Rubik's Cube of how human development works."

Because embryonic stem cells are capable of becoming virtually every type of cell in the human body, understanding how they do so might provide the chance to harness that process to make a limitless supply of specific cells for therapeutic purposes. For instance, stem cells directed down the path of blood cell development might be useful to help treat leukemias or other blood disorders.

Zambidis and colleagues are currently using their model to study the next stage in blood cell development, which in a growing embryo involves blood cell precursors moving from the yolk sac into the liver, bone marrow and thymus. Zambidis says that if blood stem cells are to be used for therapeutic purposes, they would likely come from this next stage of development.

The research was funded by grants from the National Institutes of Health and from the American Society of Clinical Oncology. Authors on the paper are Zambidis, Fred Bunz and Curt Civin of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; and Bruno Peault and Tea Soon Park of the Department of Pediatrics at the University of Pittsburgh School of Medicine.