Fetal Timeline      Maternal Timeline     News     News Archive    Sep 17, 2015 

Kyoto University scientists are casting light into the black box of human "germ cell"
development. It is hoped that their new model may lead to information in all
stages of human development, from the creation of sperm and eggs
to the process of embryo-to-adult development.
Image Credit: Kyoto University

The black box at the beginning of life

Kyoto University sheds light on how human germ cells form in the earliest stages of development.

How do these "germ cells" form, and how do they pass genetic traits from one generation to the next? Researchers at Kyoto University have created a lab-based human germ cell model of development that sheds light on some of these basic questions. Their hope is that this accomplishment may lead to a molecular-level understanding of conditions such as infertility.

Early germ cell development in humans has remained unclear for a lack of suitable experimental animal models and the inherent difficulties of studying human embryos. Published in Cell Stem Cell, the research team has now recreated human germ cell development in the laboratory using human germ cells (egg and sperm), revealing key elements and events occurring at the beginning of their life which should apply to human life.

"When I read about his work I knew I had to come back [to Japan]", said co-first author Kotaro Sasaki. He was referring to lead researcher Mitinori Saitou's previous work in the field. Sasaki, who had established a pathology career in the United States, returned to join Saitou's team in Kyoto. For this study, five laboratories collaborated at the university's Center for iPS Cell Research and Application (CiRA).

To date, most stem cell research has been restricted to mice. And while these experiments provide useful information generally applicable to all mammals, there has been a lack of information specific to humans.

To that end, Saitou's team recreated the development of human germ cells, which give rise to sperm and eggs. In addition to illustrating key transcription interactions — the first step in gene expression when a particular segment of DNA is copied into RNA and makes mRNA — and signaling events.

The scientists found that epigenetic marks — traits inherited without changing the DNA sequence — are "erased" at the beginning of germ cell development.

Explains Sasaki: "We demonstrated the early events in human germ cell development. Our work should provide a basis to gain a better understanding of how certain disorders such as infertility and growth impairment come about."

The team's model, still in its early stages, is hoped to form a foundation for continuing studies on germ cell lineage. "By further reconstituting human germ cell development in vitro, we may be able to discover the mechanisms throughout the entire developmental process from embryo to adult," says Professor Saitou.

Abstract
Highlights
•Robust induction of hPGCLCs from primed hiPSCs occurs via incipient mesoderm-like cells
•EpCAM and INTEGRINα6 are identified as markers for hPGCLC purification
•hPGCLCs avoid activation of a somatic program and undergo epigenetic reprogramming
•BLIMP1 stabilizes germline transcription and represses neuronal differentiation

Summary
Mechanisms underlying human germ cell development are unclear, partly due to difficulties in studying human embryos and lack of suitable experimental systems. Here, we show that human induced pluripotent stem cells (hiPSCs) differentiate into incipient mesoderm-like cells (iMeLCs), which robustly generate human primordial germ cell-like cells (hPGCLCs) that can be purified using the surface markers EpCAM and INTEGRINα6. The transcriptomes of hPGCLCs and primordial germ cells (PGCs) isolated from non-human primates are similar, and although specification of hPGCLCs and mouse PGCs rely on similar signaling pathways, hPGCLC specification transcriptionally activates germline fate without transiently inducing eminent somatic programs. This includes genes important for naive pluripotency and repression of key epigenetic modifiers, concomitant with epigenetic reprogramming. Accordingly, BLIMP1, which represses somatic programs in mice, activates and stabilizes a germline transcriptional circuit and represses a default neuronal differentiation program. Together, these findings provide a foundation for understanding and reconstituting human germ cell development in vitro.

The paper "Robust In Vitro Induction of Human Germ Cell Fate from Pluripotent Stem Cells" appeared in the 6 August 2015 issue of Cell Stem Cell, with doi: http://dx.doi.org/10.1016/j.stem.2015.06.014

Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigeous international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centers, as well as facilities and offices around Japan and the world. For more information please see: http://www.kyoto-u.ac.jp/en

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