Researchers at the University of Michigan in Ann Arbor have found a new method for growing stem cell colonies that mimic parts of early human development. The colonies could help investigate questions related to maternal and child health.
The technique imitates stages in embryo development that occur shortly after implantation in the uterus. This is when the amniotic sac begins to form and when the stem cells that would go on to become the fetus take their first steps toward organization into the body. The embryo-like structures in the experiment do not have the potential to develop beyond small colonies of cells.
The system can produce hundreds or thousands of embryo-like structures needed to determine whether medicines are safe for women to take during early pregnancy.
Engineers and biologists got cells to act in ways that resemble aspects of embryonic development. They developed the epiblast, a colony of stem cells that comprise most of the cells that would go on form a fetus; the beginnings of the amniotic sac and the posterior, or rear end of the epiblast that would become the lower portion of the fetus; and the beginnings of the amniotic sac and the anterior, or upper end of the epiblast that makes the upper portion of the fetus.
The second and third models, which contain the rear end and upper end of epiblast cells, only contained a portion of the epiblast cells that are present in embryos.
“Our stem cell structures that mimic embryos can help fill critical gaps in knowledge about early human development, and that could lead to a lot of good,” says Jianping Fu, associate professor of mechanical engineering and lead on the project. “This research could give us a window into the pivotal but barely observable period between two and four weeks after conception. This is a time when many miscarriages happen, and serious birth defects can form. Scientists have even begun to find connections between late-onset diseases and early development. We need to understand these processes better if we’re ever going to develop preventative measures.”
The most accurate insights about human development have, until now, come from limited studies with large animals or complete human embryos. It’s not possible to complete these studies on a large enough scale for applications like chemical and medication screening. Fu says the new system is ready to screen medications for safety in early pregnancy.
“Our lack of knowledge about how medications affect embryo development is a serious public health problem,” says Fu.
A study cited by the Centers for Disease Control and Prevention found that of the 54 most common medications pregnant women use in the first trimester, 63 percent had “very limited to fair” risk data. Only 4 percent had “good to excellent” data.
The team also hopes to find insights into the causes of some birth defects or congenital disabilities. Anencephaly, a condition in which parts of the brain and skull don’t develop, is fatal. In spina bifida, the spinal cord is damaged, and some cases result in severe disabilities. About 40,000 births per year are affected by congenital heart defects.
Because the system works with reprogrammed adult cells as well as embryonic stem cells, it may be able to make discoveries on infertility. About 30 percent of couples who seek fertility treatment don’t receive an explanation for why they haven’t conceived.
“This work provides a controllable and scalable experimental platform to ask important questions related to human development and reproduction,” Fu says. “Our findings demonstrate that human development is very different from other mammals. Different signaling pathways are involved. So, this is the only way right now to accurately study human development without using intact human embryos.”
To generate the three models, the team grew the stem cells in a scalable microfluidic system of three channels. The central channel contained a gel that mimicked the wall of the uterus. The channels on either side were for feeding in stem cells and for chemical signals that guided the cells’ development.
“In conventional 3-D cultures, less than 5 percent of the stem cell clusters would form embryo-like structures,” Fu says. “With this microfluidic system, which gives us a handle to precisely control the culture environment, we can achieve above 90 percent efficiency for generating such embryo-like structures.”
After the cells grew into colonies, they burrowed into the gel. The researchers then added chemical signals that turned them into the rear end and upper end of the epiblast.
The research was funded by the U-M Mechanical Engineering Faculty Support Grant, Michigan-Cambridge Research Initiative, University of Michigan Mcubed Fund, National Institutes of Health, and California Institute of Regenerative Medicine.
