Making stem cells feel like they are growing in the right neighborhood may be key to success

An adage in real estate says that the most important thing is neighborhood, neighborhood, neighborhood. Researchers are learning that the same may be true for stem cell therapies. If you want to mature stem cells into the right adult tissue and get them to behave the way you want, you better pay attention to the environment where they are grown in the lab—before they are transplanted into people.

Two journal articles posted online this month provide good reasons to head the realtors’ advice. CIRM-grantee Shyni Varghese at the University of California, San Diego, provides an elegantly simple example. When trying to turn embryonic stem cells into bone researchers often embed them inside a hydrogel scaffold. This helps them to stay put when transplanted. But researcjers generally rely on chemical or genetic signals to get the stem cells to mature into bone. This results in a mixed population of bone cells and fat cells because both those cell types branch from the same maturation pathway.

Varghese’s team altered the scaffold to make it seem more like the neighboring bone cells the maturing stem cells would encounter in normal bone. They mineralized it with calcium and phosphate. And when they did, they got pure bone cells in the lab dish. What’s more, when they implanted those “tissues” into animals, they formed densely calcified bone—the hard kind we want. The team published the work in the Journal of Materials Chemistry online July 4.

A review article in the journal BioResearch provided a good overview of ways various groups have tried to precondition stem cells in the lab so that they will survive after transplant. One of the biggest stumbling blocks in the field remains the difficulty of getting stem cells to survive in the patient, whether those are humans or little mouse patients. It turns out from the research cited in this review that turning the lab growth environment into something more closely resembling the environment in the patient improves survival.

Stem cell researchers need their version of the Google mapping bike to reveal the natural neighborhoods where the cells would grow.

Stem cell researchers need their version of the Google mapping bike to reveal the natural neighborhoods where the cells would grow.

They looked at several aspects of typical lab cell cultures that don’t mimic real tissue. Sites of injury where stem cells are needed often are also sites of lowered oxygen levels, inflammation and a disruption of the normal cell-to-cell contact that helps guides cell behavior. They found that adjusting each of those in the lab resulted in cells that were more likely to survive after transplant.

Most notably, when they grew cells in aggregates that restored cell-to-cell contact—restored the sense of neighborhood—cell survival improved significantly. Genetic Engineering & Biotechnology News wrote a brief summary of the work.

Don Gibbons

The Fatal Flip: How Nerve Cells go from Healthy to Cancerous

Every gene in the human genome has a job to do. One such gene, called Merlin, prevents cells from dividing out of control and forming into tumors. A so-called ‘tumor suppressor,’ Merlin has proven to be essential to maintaining healthy cell division. Scientists knew that without Merlin, nerve cells grew uncontrollably, often leading to tumors and a type of inherited cancer called neurofibromatosis type 2 (NF2).

Scientists have uncovered the mechanism whereby an absence of the gene called Merlin causes normal nerve cells to turn rogue.

Scientists have uncovered the mechanism whereby an absence of the gene called Merlin causes normal nerve cells to turn rogue.

Now, scientists have uncovered the mechanism that causes an absence of Merlin to transform nerve cells into rogue, tumor-producing cells—helping shed new light on how the smallest genetic shifts—even in just one gene—can have an impact on the normal pattern of growth and development of cells.

Reporting in the latest issue of Cancer Cell, a joint team from the Sloan-Kettering Institute for Cancer Research and Plymouth University Peninsula Schools of Medicine and Dentistry have found that without Merlin a chemical pathway, called the Hippo pathway, switches on. This, in turn, spurs tumor cell growth in nerve cells.

Professor Dr. Oliver Hanemann of Plymouth University and one of the study’s senior authors, explained in a July 22 news release:

“We have known for some time that the loss of the tumor suppressor Merlin resulted in the development of nervous system tumors, and we have come tantalizingly close to understanding how this occurs.”

This research advance is especially important in the case of NF2, a condition for which there are limited treatment options. Current treatments usually involve a combination of surgery and radiation, but rarely is the cancer fully eradicated.

“By understanding the mechanism [of Merlin], we can use this knowledge to develop effective drug therapies—in some cases adapting existing drugs—to treat patients for whom current therapies are limited and potentially devastating.”

Stem cell biology has also proven essential when shining a light on or explaining the complexities surrounding cancer’s underlying mechanisms, including the notion of cancer stem cells—a concept that has gained increasing support in recent years. To learn more about how CIRM-funded scientists are harnessing stem cells to understand—and develop treatments for—cancer, check out our 2009 Spotlight on Cancer Stem Cells as well as our Brain Tumor fact sheet.