Back in 2001, an Israeli boy suffering from Ataxia Telangiectasia, a genetic brain disease that affects movement, traveled to Russia for an unregulated stem cell treatment. Doctors injected his brain and spinal cord with fetal stem cells, though the exact composition of those cells was unknown. Four years later, the boy complained of headaches, and his doctors back home found tumors in his brain and spinal cord.

Stem cells: a double-edged sword

As the BBC  and many other news outlets reported in 2009, a Plos Medicine report eventually confirmed the tumor cells originated from the donor stem cells. And here lies a double-edged sword of stem cell-based therapies. On one side, stem cells hold great promise to repair diseased or damaged tissue because they can morph, or differentiate, into a wide range of cell types.

 On the other hand, they can remain unspecialized and continually self-renew. This helps produce enough cells to treat many people. Researchers try to ensure only more mature cells are transplanted, but if any of these propagating, undifferentiated cells are carried along with a stem cell-based treatment, there’s a risk of introducing uncontrolled cell growth and cancer instead of a remedy. Human pluripotent stem cells (hPSCs), which can form almost any cell type in the body, are believed to be especially susceptible to this dangerous side effect.

Reporting this week in the journal eLife, CIRM-funded researchers at UCSD found a way to avoid the risk of tumor growth by identifying a unique, alternative stem cell type that could be used to treat kidney disease. To find this cell type, the research team focused on cells slightly further along a differentiation path than unspecialized hPSCs.

Repeat after me: endoderm, ectoderm, mesoderm

To explain, let’s take a brief detour into developmental biology. In the earliest stages of specialization, the embryo’s cells form three germ layers: ectoderm, endoderm, and mesoderm. Each layer gives rise to specific cells and tissues. Endoderm forms, among others, the lungs, intestines, and pancreas; ectoderm develops into skin, the brain, and the spinal cord; mesoderm forms blood, muscle, bone, and kidneys. Within each germ layer lie progenitor stem cells that can self-renew and differentiate into the adult cells formed by that germ layer.

Finding a mesoderm progenitor

While labs had previously developed methods for growing ectoderm and endoderm progenitor stem cells from hPSCs, few, if any, had done the same for mesoderm. So the UCSD team systematically tested thousands of nutrient and chemical combinations to grow and differentiate hPSCs into mesoderm. Using this approach, they identified a recipe that produced mesoderm progenitor cells that could multiply and grow in population yet could not form tumors when transplanted into mice.

The research team planned to test various conditions to differentiate the progenitor cells into a wide range of mesodermal tissues. But to their surprise, when triggered to differentiate, the progenitors gave rise only to kidney cells. This limited specialization is actually desired for clinical applications, since cell therapy purity is required for human testing.

Our kidneys thank you

Putting it all together, the team has identified a cell source with unlimited self-renewal capacity that can differentiate into a very specific cell type and doesn’t carry a risk of tumor formation when transplanted. These qualities make the mesoderm progenitor cell an exciting tool for developing future kidney repair or replacement treatments. And as Dr. Karl Willert, senior author and associate professor at UC San Diego, states in a UCSD press release, there is also reason to be excited about near-term applications:

“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation. I think such a therapeutic application is still a few years in the future, but engineered kidney tissue can serve as a powerful model system to study how the human kidney interacts with and filters drugs. Such an application would be of tremendous value to the pharmaceutical industry.”