Mayo Clinic and Yale University scientists have developed a minimally invasive process for studying early cell development in a living person. The team reconstructed the cell history of two adult volunteers from just after cell fertilization. They found that in the first cell divide — 29 years earlier for one volunteer and 66 years earlier for the other — the two cells produced did not contribute equally to the development of the future adult body. These findings are reported in the journal Science.
"To find better treatments for developmental diseases, we need to have better understanding of the development itself," says co-senior author Alexej Abyzov, Ph.D., associate professor of biomedical informatics at Mayo Clinic.
Once fertilized, the cell known as a zygote begins its journey to the uterus. Along the way it divides in two. The resulting cells are each called blastomeres. But are they identical?
"The idea of the first two blastomeres being different was suggested and tested in mice," explains Dr. Abyzov. "Experiments did and didn’t support that hypothesis. Basically, there is an ongoing debate."
The debate is around the fate of those blastomeres' decedents: the cells continue to divide into tissues and eventually organs; forming a lineage from the blastomere to the final form of the cell. Cells constantly pick up mutations after fertilization throughout development and after birth, called somatic mutations. Cells can be tracked through these mutations back to their originating blastomere.
To follow the cell lineages back from adult to blastomere, the authors regressed skin fibroblast cells to a stem-cell like state, called an induced pluripotent stem cell. These cells are cultured as clonal lines, which allows the researchers to analyze the genome of the individual cells founding the clones. Then the researchers compared the lines — the fibroblast cell clones — to each other to identify mutations in each fibroblast cell. They then looked for those mutations in the other samples collected: blood, urine, and saliva. This is the first minimally invasive framework for studying early cell lineages and early development in living individuals, according to Dr. Abyzov.
In humans, Dr. Abyzov says, a 2:1 asymmetry of early blastomeres was suggested by previous research — so, one of the blastomeres contributed two cells for one from the other blastomere.
"In this work, we are the first to show that the difference between blastomeres is a dramatic 9:1 asymmetry, suggesting the first two blastomeres are different," says Yeongjun Jang, Ph.D., co-first author on the paper and a bioinformatics post-doctoral fellow in Dr. Abyzov’s lab.
In the two adult volunteers, the authors report that one of the blastomeres was responsible for 70-90% of cells in tissues, while the second provided 10-30%.
"A potential implication of this work is that one of the first two blastomeres mostly makes up our body while the other mostly makes up the placenta," Dr. Abyzov says.
If true, this finding has implications for genetic testing during the process of in vitro fertilization. Also, some conditions, such as Parkinson's Disease and Tourette Syndrome exhibit asymmetrical manifestations which could be rooted in the asymmetries during development. Next up the team plans to study asymmetries in later developmental trajectories and how they may be related to asymmetrical manifestation of disease presentation.
Funding for this work was provided by the National Institute of Mental Health. In addition to Drs. Abyzov and Jang, other authors from Mayo are Taejeong Bae, Ph.D.; Vivekananda Sarangi; Nikolaos Vasmatzis; and Yifan Wang, Ph.D. The full author list can be found in Science.