Novel Stem Cell Line Avoids Risk of Introducing Transplanted Tumors

Human pluripotent stem cells (hPSC) can become any type of cell in the adult body, offering great potential in disease modeling, drug discovery and creating replacement cells for conditions ranging from cardiovascular to Alzheimer’s disease.

Preparing stem cell lines is a balancing act. Stem cells should be highly potent, retaining the ability to differentiate into desired adult cell types. But they shouldn’t run riot. They shouldn’t form tumors.

Striking a compromise between high potency and safety, researchers based at the University of California, San Diego (UCSD) have developed a kind of cell culture that produces progenitor cells, which are early descendants of stem cells. Unlike pluripotent stem cells, which retain a high degree of differentiation ability, progenitor cells possess only limited differentiation ability. They are, in a sense, semi-potent.

Compared to populations of stem cells, populations of progenitor cells would be less likely to harbor undifferentiated cells that could seed tumor growth. Consequently, progenitor cells would constitute safer transplant or tissue-reconstruction material.

To realize the promise of progenitor cells, a UCSD scientific team led by Karl Willert, Ph.D., in collaboration with Arizona State University’s David Brafman, Ph.D., engineered an in vitro microenvironment that permitted homogenous expansion of human pluripotent stem cell (hPSC) progenitor cells from the mesoderm, one of the three primary germ layers in early embryonic development. The scientists detailed their work in an article (“Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells”) that appeared November 10 in the journal eLIFE.

“[We] used a cellular microarray technology to identify a defined and optimized culture condition that supports the derivation and propagation of a cell population with mesodermal properties,” wrote the authors. “This cell population, referred to as intermediate mesodermal progenitor (IMP) cells, is capable of unlimited expansion, lacks tumor formation potential, and, upon appropriate stimulation, readily acquires properties of a subpopulation of kidney cells.”

“Interestingly,” the authors added, “IMP cells fail to differentiate into other mesodermally-derived tissues, including blood and heart, suggesting that these cells are restricted to an intermediate mesodermal fate.”

The scientists explained that the ability to generate expandable populations of progenitor cells with limited differentiation presents several advantages over the use of undifferentiated human stem cells.

1. Cultures derived from the latter often harbor undifferentiated cells that retain the potential to seed tumor growth.

2. Development and manipulation of lineage-restricted progenitors is less elaborate. It’s easier to create mature cell populations for research or therapeutic use.

3. Because progenitor cells are limited in what kind of cell they can be, they are less likely than stem cells to differentiate into an unwanted cell type.

“This work nicely complements recent advances in tissue engineering and the goal of rebuilding or recreating functional organs, such as what we’ve seen with the creation of ‘mini-kidneys’,” said Dr. Willert. “Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation.”

Dr. Willert admitted that such therapeutic applications will likely take years to develop. But he also pointed out that in the meantime, engineered kidney tissue could serve as a powerful model system to study how the human kidney interacts with and filters drugs. “Such an application,” he insisted, “would be of tremendous value to the pharmaceutical industry.”

In the current study, the progenitor cells were evaluated only for their ability to differentiate into cells that contribute to the kidney. Nonetheless, these cells are likely capable of differentiating into other cell types of the intermediate mesodermal lineage, most notably the germ line. That is, these cells may be capable of generating eggs and sperm in a dish.

“We are now investigating to what extent these cells can generate other tissues and organs that derive from intermediate mesoderm, including reproductive organs,” noted Dr. Willert. He added that his team is pursuing similar bioengineering-based approaches to generate other similar expandable progenitor cell populations capable of differentiation into mature cell types derived from other germ layers.