麻豆传媒

News — SAN FRANCISCO, CA—As a human embryo undergoes development, certain molecules orchestrate the process of cell division and determine their unique identities and positions within the growing embryo. An essential phase called gastrulation involves these signaling molecules guiding a layer of embryonic stem cells to organize into three distinct layers of cell types. These layers will eventually differentiate into various body parts.

Recent findings from the iPS Cell Research Center at Gladstone Institutes indicate that tight junctions between cells might have a crucial impact on gastrulation in human embryos.

Shinya Yamanaka, MD, PhD, a senior investigator at Gladstone and one of the study's senior authors published in the journal Developmental Cell, expressed enthusiasm about the exciting implications of their research. He mentioned that understanding the signaling mechanisms during gastrulation could significantly enhance the design of gastrulation models and other laboratory techniques for differentiating stem cells into specialized cell types. This improved knowledge would lead to more reliable and consistent ways to replicate these processes.

The research team is already putting their findings to practical use. They are utilizing the results to develop innovative techniques that can transform stem cells into human egg cells within a laboratory setting. Such advancements hold the potential for future applications in in vitro fertilization processes.

Discovery on the Edge

Gastrulation, a pivotal process in human development, lays the groundwork for the formation of the entire body. Remarkably, researchers have managed to replicate a simplified version of this crucial event within a laboratory setting. They initiate the process using induced pluripotent stem cells (iPS cells), which are adult cells reprogrammed to emulate embryonic stem cells, capable of differentiating into any cell type.

To initiate the gastrulation-like process, scientists introduce a protein called BMP4, a significant signaling molecule during gastrulation. As a result, the cells in the laboratory dish begin organizing into the three distinct layers characteristic of embryonic development. However, a puzzling aspect remains unresolved: despite all cells receiving the same BMP4 signal, the reason behind some cells transforming into one cell type while others differentiate into different cell types remains unclear.

Ivana Vasic, PhD, the lead author of the study and a former postdoctoral researcher at Gladstone, expressed the puzzlement shared by the scientific community regarding the observed phenomenon. She mentioned, "This has been kind of a head scratcher in the field. All these cells are either interpreting the same cue from BMP4 differently, or they're not really getting the same cue."

During the creation of the gastrulation model in the laboratory, Vasic noticed that the iPS cells, clustered together in the dish, contained proteins essential for forming tight junctions—a cellular barrier between cells. However, she also observed that these tight junctions didn't always assemble as expected, adding to the intrigue surrounding the differences in cellular responses to the BMP4 cue.

Yamanaka, Vasic, and their research team made a significant discovery by altering the cell growth environment. Creating a less confined space enabled the consistent assembly of tight junctions between cells. The breakthrough came when they introduced BMP4 to the unconfined cells, leading to an "aha" moment: only the cells positioned at the cluster's edge received sufficient BMP4, activating molecular pathways that prompted them to differentiate into different cell types forming distinct layers.

Vasic explained, "Tight junctions between adjacent cells seem to shield them from signals generated by BMP4. However, the cells at the cluster's edge lack neighboring cells to form tight junctions on their outer side, leaving them more exposed to the potent cues from BMP4."

To further validate the role of tight junctions in gastrulation, the researchers utilized CRISPR genome editing technology to suppress the production of TJP1, a vital protein responsible for forming tight junctions in iPS cells. Remarkably, when they applied BMP4 to cells lacking the TJP1 protein, every single cell was activated, not just the edge cells, reinforcing the critical importance of tight junctions in this developmental process.

Yamanaka, who also serves as a professor of anatomy at UC San Francisco and director emeritus and professor at the Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan, explained their groundbreaking findings: "By removing the tight junctions, we observed that all cells responded to BMP4. This indicates that tight junctions act as barriers, preventing cells from effectively responding to signals in gastrulation models. It also highlights the fundamental importance of cellular structure in determining how cells receive differentiation signals."

Todd McDevitt, PhD, former senior investigator at Gladstone and a senior author of the study, provided additional insight: "In a broader context, this study demonstrates how modifying the inherent properties of iPS cells can influence their sensitivity to external cues and alter their developmental trajectory. This principle holds great potential for revolutionizing the use of iPS cells to generate more uniform populations of differentiated cells for therapeutic purposes."

Creating Egg Cells in a Dish

After investigating the cells activated by BMP4 when tight junction formation was altered, the team made an exciting discovery: they successfully generated a specialized type of cell known as a primordial germ cell-like cell.

Ivana Vasic expressed their excitement, stating, "We stumbled upon a very exciting finding: it turns out that we could create a special type of cell called a primordial germ cell-like cell. These cells are lab-produced stem cells that closely resemble the human precursors of sperm and egg cells."

Producing primordial germ cell-like cells has been a long-standing challenge for researchers, but Vasic and her colleagues managed to establish a novel and efficient method by suppressing TJP1, offering a promising solution.

In light of this breakthrough, Ivana Vasic has founded a new company, Vitra Labs, to explore the potential of this method in treating women's infertility. The ultimate goal is to recapitulate the biological process of egg production, providing a reliable source of eggs for in vitro fertilization.

"It's kind of the cherry on top of our study," Vasic adds with enthusiasm, recognizing the significant implications of their research in the field of reproductive medicine.