AMHERST, Mass. – A team of researchers including Yubing Sun of the University of Massachusetts Amherst has demonstrated that human pluripotent stem cells can be guided to become the precursors of the central nervous system and that mechanical signals play a key role in this process. Sun and his colleagues outlined their findings in a recent paper published in the journal Nature Materials.
The other members of the research team are Xufeng Xue, Agnes M. Resto-Irizarry, Koh Meng Aw Yong, Yi Zheng, Shinuo Weng, Yue Shao and Jianping Fu from the University of Michigan. Also, Ye Yuan, University of Science and Technology of China, Yimin Chai, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and Lorenz Studer from the Memorial Sloan-Kettering Institute.
Sun, a former doctoral student at Michigan and now an assistant professor of mechanical and industrial engineering at UMass Amherst, is a co-first author and co-corresponding author of the paper. He says identifying and understanding the role of mechanical signals in the development of patterns in the cells is a key finding. “While many current models attribute patterning of embryonic tissues to chemical gradients or cell migration, our results show that these factors may not be the only drivers. From the engineering perspective, we now know we can generate a specific tissue.”
In humans, the cells that will later differentiate into the central nervous system, including the brain and spinal cord, are known as the neural plate cells, while those that stand between the neural plate and future skin cells are called the neural plate border cells. The neural plate folds in on itself about 28 days after conception, becoming the neural tube, and the border on either side of it fuses together along its length.
In the new study, the researchers arranged human pluripotent stem cells into circular cell colonies with defined shapes and sizes. The cells were then exposed to chemicals known to coax them to differentiate into neural cells. During the differentiation process, cells in circular colonies organized themselves with neural plate cells in the middle and neural plate border cells in a ring around the outside.
“Since all of the cells in a micropatterned colony are in the same chemical environment, it’s amazing to see the cells autonomously differentiate into different cells and organize themselves into a multicellular pattern that mimics human development,” said Xufeng Xue, one of the researchers at Michigan and a co-first author of the paper.
The team observed that cells in the circular colony became more densely packed in the middle of the colony, where they became neural plate cells, versus the colony border, where they became neural plate border cells. Suspecting mechanical signals might affect their differentiation, they placed single human pluripotent stem cells onto adhesive spots of different sizes
In the same chemical environment, single human pluripotent stem cells grown on larger spots began signaling events within the cells that drove them toward becoming neural plate border cells. These signaling events were inhibited in stem cells confined on smaller spots. The team also developed a system to stretch cells in the middle of a colony. Responding to this mechanical signal, the cells in the middle of a colony differentiated into neural plate border cells, rather than the neural plate cells at the center of an ordinary colony.