生育启示：容忍是爱的一部分 老手代孕成功率更高
来源：倍可亲(backchina.com)
倍可亲科学专题：Lily
爱让世界变得更完美，但爱是世界上最复杂的事儿之一。想要维持长久的爱，懂得容忍非常重要。一对夫妻，无论如何伉俪情深，都会花很多精力来消除他们之间的分歧。母亲对孩子，爱之深爱之切，几乎不可分割，毫无保留。但母亲对孩子的容忍或耐受，却是从孩子还在母腹之中，还只是一枚小小胎儿时就已经开始了。
胎儿与妈妈有多少不同呢？从遗传方面看，胎儿的基因 50% 来自父亲，而不是来自母亲，所以事实上，胎儿对于母亲而言，算半个异体。你可以想象一下，即使父母给儿子捐肾进行肾移植，供体和受体有50%的相同基因，受体仍然需要服用免疫抑制药物来防止排斥反应。那么，妈妈的子宫里到处都是虎视眈眈的免疫细胞，为什么妈妈的子宫乐于接纳这个半异体的小东西，而不产生排斥？其主要原因是，自打从胎儿在子宫着床定居之时，妈妈的免疫系统就学着一点点地，从不间断地，从始至终地，容忍胎儿和自己的差异，直到成功分娩的那一天！
最近，辛辛那提大学医学院儿科系的Sing Sing Way博士领导的团队，用转基因小鼠模型研究了孕妈妈和胎儿之间的“爱与容忍”，以及“爱与容忍”对她们以后生育的影响。该论文于2023年9月22日发表在顶级科研期刊《Science》上，标题为“Reproductive outcomes after pregnancy-induced displacement of preexisting microchimeric cells”（https://www.science.org/doi/10.1126/science.adf9325）。
妊娠的过程异常漫长。在此期间，不断有胎儿细胞从主体上脱落下来，进入循环系统，穿过胎盘，转移到母体体内，形成胎儿微嵌合细胞。这些胎儿微嵌合细胞虽然数量很少，但包含了各种细胞，如滋养层细胞、成红细胞、白细胞、造血干细胞和间充质干细胞等。胎儿微嵌合细胞可持续地刺激母体的免疫系统，让FOXP3+调节性T细胞（Treg）被激活并在妈妈免疫器官中的扩增，从而让妈妈的子宫变得更亲切友好（哈哈，就是更能容忍胎儿）。据研究人员观察，首次怀孕的新妈妈对胎儿的耐受性相对较低，但当她第二次或第三次怀孕时，对胎儿的耐受性就大大提高了，即使后来的胎儿的遗传背景截然不同也不影响什么。为什么呢？这后面当然大有文章，详解如下。
怀孕对妈妈而言是一次身体总动员。然而，遗憾的是，当此艰巨的任务完成后（分娩后），很大一部分FOXP3+ Treg细胞就立马失业了，变成了Ex Treg细胞。我们当然知道Ex是什么意思，前任。但别小看那些Ex Treg细胞，它们都是潜伏下来，随时待命的战士！如果妈妈再次怀孕时，它们又可以重新被激活并再次扩增为FOXP3+ Treg细胞。研究者们发现，如果用某种试剂消耗掉孕妈妈体内预存在的 FOXP3+ Treg细胞，孕妈妈仍可保持良好的胎儿耐受性。但是当预存在的 FOXP3+ Treg和 Ex Treg 细胞都被消耗尽，孕妈妈对胎儿的耐受能力就会大打折扣，这对胎儿来说，真是厄运降临。因此，永远不要小看前任。
我们花了这么多篇幅讲述容忍，那妈妈的爱体现在哪里？这里，我们只准备聊聊妈妈对女儿的影响，好赖这也是一个生育为主题的故事。妈妈的子宫，不光为胎儿提供了舒适的栖息之地和充足的营养，母体的细胞也会不断地突破胎盘而进入胎儿体内，形成母体微嵌合细胞。大多数母体微嵌合细胞由免疫相关细胞、终末分化细胞和干细胞样增殖细胞等组成。这些母体微嵌合细胞可以刺激胎儿中具有非遗传性母体抗原（NIMA）特异性的 FOXP3+ Treg 细胞的扩增，帮助女儿在将来怀孕时形成免疫耐受。有些情况下，NIMA 特异性 FOXP3+ Treg 细胞真的很重要。比如，女儿长大成人后与 NIMA 匹配的男性结婚，她初次怀上了NIMA匹配的爱情结晶，她对这个胎儿的耐受性就会比较强，反之如果她怀上的宝宝来自NIMA 不匹配的男性，她对NIMA不匹配的宝宝耐受性就比较低。不过，一旦女儿怀孕后，她体内的母体微嵌合细胞就会逐渐被她自己宝宝的胎儿微嵌合细胞取代。作为妈妈，尽管女儿抹掉了很多妈妈的印记，妈妈仍应为女儿感到骄傲。女儿不是已经独挡一面了么？
从这项研究我们可以得到哪些启示呢？第一大启示可能是，爱允许差异的存在，但是差异要潜移默化、润物细无声地到来，而不是突然介入------任何剧烈改变都只会导致行动的流产。第二，如果一对夫妇正在寻找一位代孕妈妈来孕育他们爱情的结晶 （像香港著名美女主持和前最高外交官那样），他们应该选择一位经历过多次怀孕和分娩的代孕老手，而不是一个从未生育的新妈妈。第三，听起来可能有点怪，如果代孕妈妈与胎儿的生理学父母有血缘关系，代孕的成功率可能会更高，因为代孕妈妈和婴儿有匹配的NIMA的几率更大。
对了，“NIMA”的中文发音就是“你妈”，这个巧合也太可爱了！
Tolerance is Part of Love: A Tale of Fertility
BackChina Science Lily
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!
