To investigate the factors that threaten the success of a cow’s pregnancy, researchers at the University of Sao Paulo (USP) in Brazil have used certain chips to mimic the environment of the endometrium, the tissue that lines the uterus. did.
The study was conducted by biologist Tiago Enrique Kamala de Bem, a postdoctoral fellow at the University of Sao Paulo School of Animal Science and Food Engineering (FZEA-USP), in collaboration with four researchers at the University of Leeds in the United Kingdom. ..Their findings are reported in journal articles Endocrinology..
Researchers focused on analyzing changes in insulin and glucose levels in the maternal epithelium and stroma cell,and pregnancyEpithelial cells are located on the outermost side of the endometrium. They are in contact with the lumen and in direct contact with the embryo. Stromal cells are further inside and function as supporting cells that guide the growth, differentiation, and development of epithelial cells.
The group found that high levels of glucose altered the genes that code for 21 proteins in the body. Epithelial cells And 191 are stromal cells and cause quantitative changes in the protein secretome (a protein secreted into the culture medium, in this case mimicking the endometrial fluid). “By changing the amount of glucose and insulin in the medium to stress the cells, we were able to turn the gene on and off to determine if it was expressed,” said Camara de Bem. I will.
Changes in insulin levels altered the quantitative secretion of 196 proteins, but resulted in limited alterations in gene transcription. “A key factor could be the protein composition of the uterine fluid, in which these cells secrete protein into the embryo,” he explained. “We found that this group of proteins is associated with signaling pathways that play an important role in the success of cattle in early pregnancy in relation to metabolism, cellular matrix, and other factors. All demonstrate the mechanism by which changes in maternal glucose and insulin affect the uterus. It works. “
Camara de Bem supports FAPESP through postdoctoral fellows in a project conducted at the Institute for Molecular Morphology and Development under the supervision of Professor Flávio Vieira Meirelles and an Overseas Research Internship (BEPE) scholarship. received.
According to Camara de Bem, Brazil is the world leader in bovine embryo production, but still has a high pregnancy rate. “Most of our embryos are produced by in vitro fertilization. Oocytes are collected, matured, fertilized, cultured and transferred to synchronized recipients, but 40% of pregnancies are in the third. It will be lost in the week or the fourth week, “he recalled. Cows are pregnant for about nine months, just like humans.
Reproductive success depends on many conditions. “Pregnancy is the interaction between the mother and the embryo that develops in the mother’s womb,” said Kamala de Bem. “This is a crosstalk between embryonic cells and the mother’s cells. This communication is affected by multiple processes. If the communication is incorrect, that is, if the embryo does not recognize its presence, or if the mother does not, pregnancy loss can occur. There is a developing embryo. “
He continued that environmental and nutritional problems, as well as stress from the production process itself, could disrupt maternal-embryo communication and disrupt pregnancy. In the case of cows, high-yielding dairy cows Pregnancy is a major problem and the mother’s energy balance is negative, so the first period after childbirth is often accompanied by metabolic stress.
“For example, glucose is the basic substrate for cell metabolism,” says Camara de Bem. “Cells need glucose to perform their function. Lactating cows undergo metabolic challenges to produce milk. The basic function of the organism and all functions related to milk production. It consumes a lot of energy because it needs to be maintained. Maternal metabolism has a significant effect on reproduction. Therefore, we focus on understanding the factors that cause metabolic stress in the environment that accepts embryos. I am.
Endometrium on the tip
Camara de Bem emphasized that the study was carried out in collaboration with a group led by Niamh Forde, a professor at the University of Leeds School of Medicine and the last author of this article. “She is investigating the mother’s perception of cow pregnancy. I am interested in investigating the signals that the embryo sends to the mother. We think this would be a good collaboration,” on the chip. I came up with this idea of developing the “endometrium”. It is used in multicellular cultures, that is, to grow multiple types of cells from the endometrium, “he said.
The tip is similar to a histology slide, except that it is divided into chambers (compartments) where scientists seed two types of cells. The dividers are made of a porous membrane that allows information to be exchanged between two cell types cultured in different chambers, but the cell types cannot switch positions. This device can be thought of as a commercially available chip adapted to simulate the endometrium.
“Seeding epithelial cells in the upper chamber, Stromal cells Both cell types are abundant in the endometrium. The medium in the upper chamber was enriched with factors produced and secreted by epithelial cells representing the endometrial secretome. “
With this chip, scientists always have cells Culture medium“We cultured the cells for 3 days, during which time we infused the medium. [one microliter per minute for 72 hours] He administered three glucose levels or two different levels of insulin. ” This ensured that cells were exposed to the same levels of glucose and insulin throughout the experiment. “
This method is innovative and has never been used to mimic the endometrium of cattle. Traditional cell cultures are too simple to simulate all endometrial conditions. “The endometrium is three-dimensional, and several types of cells and glands produce the factors and nutrients that help maintain pregnancy,” recalled Camara de Bem. “In vitro fertilization embryo culture using traditional methods is static and uses a single cell type in an environment that does not reflect the richness of animal organisms. Cell growth and embryo recipes It can be transplanted into embryos to produce healthy animals, but we have come out to reproduce the process in a way that is as close as possible to physiological reality. ”
Camara de Bem said his partner at the University of Leeds is developing another type of chip for embryo insertion. “This methodology opens up a wealth of opportunities. In the future, cells and embryos can be cultured together to see exactly what happens when there is a change in the medium and communication with the maternal cells. I hope I can do it. This is an opening. For more applied research, “he said.
This group of studies could also serve as a model for pregnancy studies in mammals, including humans. “With the exception of non-human primates, mice are the primary model for studying humans. Mice placental formation is most similar to the process in humans. On the other hand, unlike us, mice have There are many offspring. In cattle, placental formation is very different. It is the same as in humans, but the duration of pregnancy is similar, and only one mouse gives birth to a single pregnancy. Differences between species There is never an ideal model for this, but this can be another model, “he said.
For more information:
Tiago HC De Bem et al., Endometrium On-a-Chip, reveals insulin- and glucose-induced changes in transcriptome and proteomics secretome. Endocrinology (2021). DOI: 10.1210 / endocr / bqab054
Quote: A tip that mimics the bovine endometrium used to study factors that may endanger pregnancy (June 7, 2021)
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A tip that mimics the endometrium of a bovine used to study factors that may endanger pregnancy
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