New lab-made stem cells may be key to transplants

December 25, 2000

The new cells..."will be the workhorses that carry out the new tissue-transplant therapies"

The scientists at Johns Hopkins who, in 1998, showed that human pluripotent stem cells (hPSCs) --humans' earliest, undifferentiated "full potential" cells -- could develop into all the basic types of embryonic tissues that make up human beings, have now "engineered" hPSCs to form a new type of cell that not only holds the potential to develop into different tissues but also overcomes great drawbacks that have limited the use of hPSCs for disease therapy.

The new cells, called embryoid body derived cells (EBDs), "will be the workhorses that carry out the new tissue-transplant therapies," says John D. Gearhart, Ph.D., the Hopkins team leader.

"The first applications of these cells will likely be in Lou Gehrig's disease (ALS), Type I diabetes, stroke and Parkinson's disease," says Gearhart. Researchers in other Hopkins labs have already begun testing EBDs on animal models of Lou Gehrig's and other neurodegenerative diseases, as well as on animal spinal injuries.

EBDs reproduce readily and are easily maintained, Gearhart said, and thus eliminate the need to use fetal tissues each time as a source -- a step that should quell many of the political and ethical concerns that swirl around stem cell studies.

"We thought from the first that problems would arise using hPSCs to make replacement tissues," says molecular biologist Michael Shamblott, Ph.D. The early-stage stem cells are both difficult and slow to grow. "More important," says Shamblott, "there's a risk of tumors.

If you're not very careful when coaxing these early cells to differentiate -- to form nerve cells and the like -- you risk contaminating the newly differentiated cells with the stem cells. Injected into the body, stem cells can produce tumors. The EBDs bypass all this."

EBDs readily divide for up to 70 generations, producing millions of cells without any apparent chromosomal abnormalities typical of tumor cells. No tumors appeared in three cancer-prone test mice injected with the new cells.

Moreover, EBD cells appear to accept "foreign" genes readily -- a necessity, Shamblott says, for scientists to produce large quantities of differentiated "replacement" cells for human transplants.

The researchers began their work with embryonic germ cells, a type of hPSC drawn from discarded fetal tissue. In culture, the germ cells grow into a small mass of cells called an embryoid body. After teasing the embryoid bodies apart using gentle enzymes, the scientists cultured the separated cells in one of six "very simple growth environments."

Sample cells from each environment -- now called embryoid body derived cells -- were grown again, this time in culture solutions that favored growth of specific cell lines, such as nerve cells, and allowed to divide undisturbed for many generations.

The researchers quickly recognized EBD cells' ability to grow readily, but hadn't a clear idea what they'd produced. To their surprise, tests to identify molecules characteristic of specific cell types revealed markers from at least four basic mammalian cell lines, including those that give rise to neural (nerve) cells, muscle and blood.

The researchers believe they have made a sort of biologic raw material which, when placed within specific environments in the body, will be prodded to differentiate into specific tissues.
Other researchers were: John W. Littlefield, M.D., Paul A. Blumenthal, M.D., George R. Huggins, Ph.D., Yan Cui, Ph.D., Linzhao Cheng, Ph.D, and Joyce Axelman.

Geron, Inc. provided funding for the study. Under a licensing agreement between Geron and Johns Hopkins University, the University and John Gearhart and Michael Shamblott are entitled to a share of sales royalty from Geron.

The University and John Gearhart and Michael Shamblott own stock in Geron, the sale of which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the University in accordance with its conflict-of-interest policies.

To get a copy of the research paper, reporters should contact PNAS directly at 202-334-3741.

JHMI Media contact: Marjorie Centofanti 410-955-8725 or Karen Blum at 410-955-1534.

Johns Hopkins Medicine

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