UCSD School of Medicine

UCSD researchers use stem cell model to better understand pregnancy complication

/ Yimy Villa / Leave a comment
A team of UC San Diego researchers recently published novel preeclampsia models to aid in understanding this pregnancy complication that occurs in one of 25 U.S. pregnancies. Researchers include (left to right): Ojeni Touma, Mariko Horii, Robert Morey and Tony Bui. Credit: UC San Diego

Pregnant women often tread uncertain waters in regards to their health and well-being as well as that of their babies. Many conditions can arise and one of these is preeclampsia, a type of pregnancy complication that occurs in approximately one in 25 pregnancies in the United States according to the Center for Disease Control (CDC). It occurs when expecting mothers develop high blood pressure, typically after 20 weeks of pregnancy, and that in turn reduces the blood supply to the baby. This can lead to serious, even fatal, complications for both the mother and baby.

A CIRM supported study using induced pluripotent stem cells (iPSCs), a kind of stem cell that can turn into virtually any cell type, was able to create a “disease in a dish” model in order to better understand preeclampsia.

Credit: UC San Diego

For this study, Mariko Horii, M.D., and her team of researchers at the UC San Diego School of Medicine obtained cells from the placenta of babies born under preeclampsia conditions. These cells were then “reprogrammed” into a stem cell-like state, otherwise known as iPSCs. The iPSCs were then turned into cells resembling placental cells in early pregnancy. This enabled the team to create the preeclampsia “disease in the dish” model. Using this model, they were then able to study the processes that cause, result from, or are otherwise associated with preeclampsia.

The findings revealed that cellular defects observed are related to an abnormal response in the environment in the womb. Specifically, they found that preeclampsia was associated with a low-oxygen environment in the uterus. The researchers used a computer modeling system at UC San Diego known as Comet to detail the differences between normal and preeclampsia placental tissue.

Horii and her team hope that these findings not only shed more light on the environment in the womb observed in preeclampsia, but also provided insight for future development of diagnostic tools and identification of potential medications. Furthermore, they hope that their iPSC disease model can be used to study other placenta-associated pregnancy disorders such as fetal growth restriction, miscarriage, and preterm birth.

The team’s next steps are to develop a 3D model to better study the relationship between environment and development of placental disease.

In a news release from UC San Diego, Horri elaborates more on these future goals.

“Currently, model systems are in two-dimensional cultures with single-cell types, which are hard to study as the placenta consists of maternal and fetal cells with multiple cell types, such as placental cells (fetal origin), maternal immune cells and maternal endometrial cells. Combining these cell types together into a three-dimensional structure will lead to a better understanding of the more complex interactions and cell-to-cell signaling, which can then be applied to the disease setting to further understand pathophysiology.”

The full study was published in Scientific Reports.

DNA therapeutic treats blood cancer in mice and begins human clinical trial

/ Yimy Villa / 1 Comment
The left image represents a microscopic view of the bone marrow of a myeloma-bearing mouse treated with control, and the right image represents the same for a myeloma-bearing mouse treated with ION251, an experimental therapeutic. The red dots represent the IRF4 protein within human myeloma cells, which are much sparser after ION251 treatment. Image credit: UC San Diego Health

Multiple myeloma is the second most common blood cancer in the United States, with more than 32,000 new cases predicted in 2020.  Unfortunately, many patients with this type of blood cancer eventually develop resistance to multiple types of treatments.  This phenomenon is partially due to the fact that cancer stem cells, which have the ability to evade traditional therapies and then self-renew, help drive the disease.

It is for this reason that a team of researchers, at the UC San Diego School of Medicine and Ionis Pharmaceuticals, are developing a therapy that can destroy these malignant stem cells, thereby preventing the cancer from coming back.  With support from CIRM, the team developed an approach that interacts with IRF4, a gene that allows myeloma stem cells and tumor cells to grow and survive chemotherapy and radiation.  They have engineered an oligonucleotide, a short DNA molecule, to prevent IRF4 from functioning.  The therapy, known as ION251, lowered disease burden, reduced the amount of myeloma stem cells, and increased survival when tested in mice bearing human myeloma.  These results have enabled the team to start a Phase I clinical trial to see if this approach is safe and effective in people with myeloma.

To study the disease and test ION251, the team transplanted human myeloma cells into mice that lack an immune system and thus won’t reject human cells.  Ten mice received the ION251 treatment and an additional ten mice received a control treatment.  After receiving the ION251 therapy, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment.  Additionally, 70 to 100 percent of the treated mice survived, whereas none of the untreated control mice did. 

In a news release from UC San Diego Health, Dr. Leslie Crews, co-senior author and assistant professor at the UCSD School of Medicine, elaborated on the promising results from the mouse study.

“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank — in the treated mice, we couldn’t find any myeloma cells left for us to study.  It makes the science more difficult, but it gives me hope for patients.”

The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere. More information on this can be viewed by clicking the link here.

The full results of this study were published in the journal Cell Stem Cell.

Lab-grown human sperm cells could unlock treatments for infertility

/ Kevin McCormack / 1 Comment
Dr. Miles Wilkinson: Photo courtesy UCSD

Out of 100 couples in the US, around 12 or 13 will have trouble starting a family. In one third of those cases the problem is male infertility (one third is female infertility and the other third is a combination of factors). In the past treatment options for men were often limited. Now a new study out of the University of California San Diego (UCSD) could help lead to treatments to help these previously infertile men have children of their own.

The study, led by Dr. Miles Wilkinson of UCSD School of Medicine, targeted spermatogonial stem cells (SSCs), which are the cells that develop into sperm. In the past it was hard to isolate these SSCs from other cells in the testes. However, using a process called single cell RNA sequencing – which is like taking a photo of all the gene expression happening in one cell at a precise moment – the team were able to identify the SSCs.

In a news release Dr. Wilkinson, the senior author of the study, says this is a big advance on previous methods: “We think our approach — which is backed up by several techniques, including single-cell RNA-sequencing analysis — is a significant step toward bringing SSC therapy into the clinic.”

Identifying the SSCs was just the first step. Next the team wanted to find a way to be able to take those cells and grow and multiply them in the lab, an important step in having enough cells to be able to treat infertility.

So, they tested the cells in the lab and identified something called the AKT pathway, which controls cell division and survival. By blocking the AKT pathway they were able to keep the SSCs alive and growing for a month. Next they hope to build on the knowledge and expand the cells for even longer so they could be used in a clinical setting.

This image has an empty alt attribute; its file name is wilkinson-ssc-graphic_450px.jpg
Illustrations by Vishaala Wilkinson

The hope is that this could ultimately lead to treatments for men whose bodies don’t produce sperm cells, or enough sperms cells to make them fertile. It could also help children going through cancer therapy which can destroy their ability to have children of their own later in life. By taking sperm cells and freezing them, they could later be grown and expanded in the lab and injected back into the testes to restore sperm production.

The study is published in the journal Proceedings of the National Academy of Science.