Love makes our world more perfect, yet it remains one of the most intricated challenges we encounter.

In order to keep a harmonious love relationship, tolerance often assumes a crucial role. A husband and a

wife, no matter how deeply they love each other, may spend a lot of time digesting their disagreements.

A mother and her children, almost bounded by unbreakable, nearly unconditional love, the capacity of

tolerance has started to play in the mother ever since the child is still a tiny fetus in her womb.

Consider how different is a fetus from a mother. Genetically, 50% of the fetus is derived from the father

but not from the mother, making it, literally, semi-allogeneic to its mother. Imagine a kidney transplant

between a parent and a child who shares 50% genetic similarity. Even in such a scenario, the recipient

still needs to rely on immunosuppressive drugs to prevent allogeneic rejection. So, why is a mother’s

womb, guarded by millions of hostile immune cells, happy to host this half-foreign little guy and does

not reject it? The primary reason is that the mother’s immune system has learned to tolerate the

distinctions between the fetus and herself, little by little, steadily and continuously, starting from the

moment of implantation and persisting until a successful parturition!

Recently research has clearly described the “love and tolerance” shared between mothers and fetuses

during pregnancy, along with its impact on their later fertility. The study was conducted using transgenic

mouse models under the leadership of Dr. Sing Sing Way from the Department of Pediatrics at the

University of Cincinnati College of Medicine. The paper was published on September 22 , 2023 in the

prestigious research journal Science, under the title " Reproductive outcomes after pregnancy-induced

displacement of preexisting microchimeric cells”

(https://www.science.org/doi/10.1126/science.adf9325).

The research indicated that, during the lengthy process of pregnancy, some fetal cells could

continuously detach from the fetuses’ main bodies, enter the circulation, cross the placenta, be

transferred to the mother, and form fetal microchimeric cells inside her. Those fetal microchimeric cells,

although present in small numbers, could include various cell types, such as trophoblasts, erythroblasts,

leukocytes, haemopoietic and mesenchymal stem cells, and continuously stimulated the mother’s

immune system. Consequently, FOXP3+ regulatory T (Treg) cells were activated and expanded in the

mother’s immune organs, aiding the uterus maintaining a welcoming and accommodating environment

for the fetuses (tolerating the fetuses, ha-ha). The researchers observed that a young female becoming a

mother for the first time exhibited lower fetal tolerance, while her tolerance to fetuses significantly

improved during her second or third pregnancy, even when the later fetuses had a completely different

genetic background. Undoubtably, there are numerous mechanisms underlying these findings.

Pregnancy subjected the mother’s body to an all-encompassing transformation. Unfortunately, once the

arduous task was completed, a large percentage of FOXP3+ Treg cells lost their jobs after the parturition

and transformed into Ex Treg cells (we assume the meaning “Ex” is clear, right?). Don’t underestimate

those Ex Treg cells, because they were standby warriors, retaining the potential to revert to FOXP3+ Treg

cells when the mother became pregnant again! It was discovered that if pre-existing FOXP3+ Treg cells

were depleted in a pregnant mother using certain chemicals, the mother still exhibited reasonable fetal

tolerance. However, when both pre-existing FOXP3+ Treg cells and Ex Treg cells were depleted, the

mother’s ability to tolerate fetuses decreased dramatically, which was a real doom to the fetuses. So,

never underestimate the Ex.

So far, we have dedicated several paragraphs to discussing tolerance, but where is the mother’s love in

all of this? Well, let’s shift our focus solely on the impact mothers have on their daughters, after all, this

is a tale of fertility. Besides providing a comfortable dwelling place and sufficient nutrition to the

fetuses, maternal cells continuously breached the placenta during pregnancy and entered the fetuses,

giving rise to maternal microchimeric cells. The majority of maternal microchimeric cells comprised

immune-related cells, terminally differentiated cells, and stem cell-like proliferating cells. Those

maternal microchimeric cells could also stimulate the expansion of FOXP3+ Treg cells with non-inherited

maternal antigen (NIMA) specificity in the fetuses, assisting the daughters to develop immune tolerance

in their future pregnancies. On certain occasions, the NIMA-specific FOXP3+ Treg cells were proved to be

truly crucial. For instance, if the grown-up daughter married a NIMA-matched male, she would

experience better fetal tolerance during her first pregnancy than if she was carrying a NIMA-mismatch

male’s fetuses. However, once the daughter became pregnant, the maternal microchimeric cells in her

body would be gradually displaced by fetal microchimeric cells from her own offsprings. As a mother,

even if her daughter has erased many of her marks, the mother should still be proud because now her

daughter is carrying everything on her own!

What are the direct implications for us from this fertility story? The most significant lesson should be

that love allows acceptance of differences. However, these differences should be introduced

imperceptibly, rather than suddenly or drastically, as this could lead to a miscarriage of the mission.

Second, if a couple is looking for a surrogate mom to bring their love’s creation to the world (like the

choice between the famous beautiful Hongkong TV host and the Ex highest-ranking diplomat), they

should choose a veteran on this profession, who has undergone pregnancy and childbirth multiple

times, rather than a newcomer who has never been pregnant before. Thirdly, it may sound unusual, but

if a surrogate mom is biologically relative to either the father or mother, the surrogacy may have a

higher success rate. This is because the surrogate mother and the baby might have a better chance of

carrying matched NIMA.

By the way, “NIMA” in Chinese pronunciation, means “your mom”. What a lovely coincidence!