Mesoderm Progenitor Cells With Reduced Tumor-Causing Potential Derived from Human Pluripotent Stem Cells

Karl Willert, PhD, associate professor in the Department of Cellular and Molecular Medicine at the University of California, San Diego and his colleagues have generated a new cell line in his laboratory that can potentially all the tissues in our bodies that are generated from mesoderm.

During embryonic development, 14 days after fertilization, the embryo is transformed from a single-cell thick sheet to a three-layered structure by a process called gastrulation. Gastrulation forms an outer layer of cells known as the ectoderm, which forms the skin and the nervous system, a middle layer of cells known as the mesoderm, which forms the muscles, heart, blood vessels, kidneys, gonads, dermis, adrenal glands, bones, and several other important tissues, and an innermost layer of cells called the endoderm, which forms the gastrointestinal tract as its associated structures. These three layers, the ectoderm, mesoderm, and the endoderm, are collectively known as the “primary germ layers” and they are formed at gastrulation.

Willert, in collaboration with co-corresponding author David Brafman from Arizona State University, used a high-throughput screening platform that had been previously developed in Brafman’s laboratory to define the exact cellular microenvironment that would drive pluripotent stem cells efficiently differentiate into mesodermal progenitor cells. Such cells could theoretically differentiate into any of the derivatives of the mesodermal germ layer, and these cells would also show a greatly reduced capacity to form tumors, since they are no longer pluripotent, but only multipotent.

After using their screening platform to differentiate human embryonic stem cells into cells that expressed mesodermal-specific genes, Willert and his team settled upon a microenvironment that differentiated these stem cells into intermediate mesodermal progenitor (IMP) cells that could be propagated in culture. Interestingly, these IMP cells had the ability to differentiate into mature kidney cells, without the risk of forming tumors. Oddly, these cells were not able to differentiate into other types of mesodermal derivatives.

“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 Willert. “It represents a novel source of cells.” This study was published November 10, 2015 in the online journal eLIFE.

Extensive analyses showed that their IMP cells lacked tumor-forming potential. However, they retained the ability to differentiate into cells that compose the adult kidney. The ability to generate expandable populations of IMPs cells with limited differentiation have several advantages over pluripotent human stem cell cultures. First, pluripotent stem cell cultures can be differentiate into specific cell types but even under the best of conditions, such cell preparations can harbor undifferentiated cells that retain the potential to seed tumor growth. Secondly, it is much easier to manipulate and differentiate IMP cells than pluripotent stem cells. That simplifies the protocols for handling these cells, which also decreases the time and expense required to make anything from these cells.  Third, since IMP cells have limited differentiation capabilities, they are less likely than pluripotent stem cells to differentiate into unwanted cell types.

“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation,” said Willert. “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.”

Even though Willert’s IMP cells differentiated into kidney cells, Willert is optimistic that they are capable of differentiating into other mesodermal-derived cell types, like gonads. “We have only characterized their potential to differentiate into cells that contribute to the kidney. We are now investigating to what extent these cells can generate other tissues and organs that derive from intermediate mesoderm, including reproductive organs.”

Willert and his colleagues are using the same protocol to generate other expandable progenitor cell lines from pluripotent stem cells derived from other germ layers, such as ectoderm and endoderm.