In first, Hebrew U. lab induces placenta cells, boosting pregnancy disorder research

Achievement will allow study of possible causes for placental insufficiency, which affects up to 15% of pregnancies and causes one in 100 pregnancies to end in miscarriage

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Placenta multinucleated cells (Moriyah Naama/Buganim Lab Hebrew University)
Placenta multinucleated cells (Moriyah Naama/Buganim Lab Hebrew University)

Scientists at the Hebrew University have succeeded in converting human skin cells into functioning human placenta cells, a breakthrough they say may improve the understanding of fetal development, pregnancy-related diseases and infertility, and could be used to advance gene therapies.

Prof. Yossi Buganim and his team are hopeful that their achievement could lead to a better understanding and treatment of placental insufficiency, which occurs in 10-15 percent of pregnancies and leads to miscarriage in one out of 100 pregnancies.

Placental insufficiency (also known as placental dysfunction) occurs when the embryo does not receive enough oxygen and nutrients from the placenta, resulting in restricted fetal growth and development. Complications of placental insufficiency include pre-term labor, pre-eclampsia and stillbirth, among others.

But studying the problem was difficult, Buganim said, due to the nature of the disorder. To deal with the issue, the team converted skin cells to placental stem cells, and then later into differentiated placenta cells in the lab.

“Once you discover a pregnancy disorder or complication, it’s already too late in the pregnancy because there are no stem cells to isolate anymore,” Buganim said.

“You cannot study what went wrong in the development of the embryo or the placenta. You can’t study the earliest stages because you don’t have the stem cells and learn what might have been problematic with the implantation [in the uterus], for example,” he said.

Prof. Yossi Buganim (Moriyah Naama/Buganim Lab Hebrew University)

The study, published in the peer-reviewed Nature Communications journal, reports how MD-PhD candidate Dr. Moriyah Naama, PhD student Moran Rahamim, and other members of the Buganim lab turned human skin cells from adult men and women, as well as foreskins from Shaare Zedek Medical Center, into placenta cells by introducing a “cocktail” of four genes. The technique is epigenetic and does not change the genome.

Buganim’s approach involves inducing early-stage placenta cells known as trophoblasts, which are critical for implantation, from skin cells, or fibroblasts. The team managed to do so without using IPS, a technique that reprograms skin or blood cells back to an embryonic-like pluripotent state that enables the development of any type of human cell needed for therapeutic purposes.

“We are the first to do this with human skin cells, and we were the first to do it in mice back in 2015,” Buganim said.

Simple over-the-counter pregnancy tests were used to confirm that the skin cells had indeed changed into placenta cells.

Dr. Moriyah Naama and Moran Rahamim check positive pregnancy test confirming that skin cells have been transformed into human placenta. (Moriyah Naama/Buganim Lab Hebrew University)

“The placenta cells are responsible for the secretion of human chorionic gonadotropin (hCG), which is what these pregnancy tests measure. We just dipped the commercial tests into the medium with the cells and saw that they were positive,” Buganim said.

The cells were then deeply characterized, including checking gene expression, epigenetic landscape and functionality.

What has been accomplished thus far is a proof of concept. According to Buganim, the next step is to develop a technique to take skin cells from embryos or babies affected by placental insufficiency and convert them into placenta stem cells for study, hopefully leading to improved diagnostics and therapies.

“By isolating the fibroblasts and converting them into placenta stem cells, we can test gene expression, their function — if they implant or don’t, if they divide or not, if they secrete important factor or not — and more,”  Buganim said.

Induced placental stem cells – green is membrane and red is protein. (Moriyah Naama/Buganim Lab Hebrew University)

His lab is working on this project with the support of Prof. Simcha Yagel’s lab at the Hadassah Medical Organization’s obstetrics and gynecology department, as well as the stem cell research laboratory at Shaare Zedek Medical Center, led by Prof. Rachel Eiges. Among other things, they are helping him to source samples of fibroblasts from babies affected by placental insufficiency, as well as from their umbilical cords and placentas.

“The placenta comes from the embryo, so I cannot take skin cell samples from a mother. It is possible for me, however, to take skin cells from an adult who suffered from placental insufficiency in the womb,” Buganim said.

Another source is IVF-conceived embryos undergoing preimplantation genetic diagnosis. At this stage, the embryos are only eight-cell clusters, and any “bad” cells are removed and given to researchers. Buganim’s lab used the cells as controls for his experiments.

Buganim predicted that his method of converting skin cells into trophoblasts would pave the way for clinical advances in the diagnosis or treatment of pregnancy-related disorders.

“I will be able to identify new markers for a complication, suggest new drugs that can rescue a pregnancy, and tell whether a couple’s next pregnancy will be problematic or not,” he said.

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