REVIEW ARTICLE
Year : 2021 | Volume
: 8 | Issue : 1 | Page : 1--8
The outcomes of fetal cell microchimerism in the mother
Anushka Nikhil Alekar
Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS (Deemed-to-be) University, Mumbai, Maharashtra, India
Correspondence Address:
Ms. Anushka Nikhil Alekar
V. L, Pherozeshah Mehta Road, Vile Parle, Mumbai - 400 056, Maharashtra
India
Abstract
The presence of small quantities of genetically heterogeneous cells in an organism is known as microchimerism. Fetal microchimerism is the presence of small quantities of fetal cells in the maternal system during and after pregnancy. Since these cells are semi-allogeneic in the mother's body, they have an impact on the mother's health. Recent studies suggest contradictory outcomes. Some suggest an involvement in autoimmune diseases and cancer. Others suggest involvement in tissue repair and wound healing. Fetal cells have been detected in maternal organs decades after pregnancy. It was found that these cells participate in the healing process post a chronic injury. In other cases, these cells initiate an immune response which may lead to the development of autoimmune diseases. Further, studies show that fetal cells have been discovered in the tumor microenvironment, either aiding in cancer development or eradicating the cancer cells. Here, I review the different outcomes that can occur in the female body because of fetal cell microchimerism. I discuss the presence of fetal cells in maternal organs such as the heart and the central nervous system organs and their involvement in disease development and tissue repair in the mother.
How to cite this article:
Alekar AN. The outcomes of fetal cell microchimerism in the mother.Biomed Res J 2021;8:1-8
|
How to cite this URL:
Alekar AN. The outcomes of fetal cell microchimerism in the mother. Biomed Res J [serial online] 2021 [cited 2023 Jun 8 ];8:1-8
Available from: https://www.brjnmims.org/text.asp?2021/8/1/1/320133 |
Full Text
Introduction
Microchimerism is the existence of minute quantities of genetically distinct cells in an organism.[1] Microchimerism occurs through many mechanisms. In placental mammals, during pregnancy, cells are exchanged between the mother and the fetus. The fetus is more invasive, and a greater number of cells are transferred, before placentogenesis, from the fetus to the mother.[2] The relationship between the mother and the fetus is both of cooperation and competition.[3] The conflict arises in the management of resources between the two systems. The impact of microchimerism on the mother is subject to controversy. Some studies suggest that fetal cells are bystanders; others suggest that these cells may eventually aid in tissue repair of maternal tissues. Whereas, some studies suggest the role of persistent fetal cells in autoimmune diseases and cancer prognosis.
The placenta is a composite organ, formed from maternal and fetal cells. It is formed when syncytiotrophoblasts invade the endometrium.[4] The purpose of the placenta is to aid in nutrient transport. It is suggested that fetal cells can infiltrate maternal organs and tissues in a similar manner. Microchimeric fetal cells can be thought of as an expansion of the placenta. A study hypothesizes that the fetal cells manipulate the maternal system into nurturing the offspring. The maternal system does not behave as a passive system; it retaliates through the immune system, but the fetal cells get the upper hand in most cases. Fetal cells that migrate to the maternal circulation are multipotent. As a result, they can differentiate into many cell types. Cell types that migrate to the maternal circulation during pregnancy include trophoblasts, erythroblasts, lymphocytes, hematopoietic stem cells (HSCs), and mesenchymal stem cells. In studies regarding chronic organ injuries or inflammation, it was found that the fetal cells participated in tissue repair and wound healing. The cells may also add to the stem cell reservoir, thus postponing maternal aging. From an evolutionary standpoint, the two mechanisms enable the mother to take better care of her offspring.
Fetal cells have been detected in many organs and tissues [Figure 1]. In the breast tissue, their function could be to enhance lactation, but they are also associated with breast carcinoma. In the thyroid gland, the function could be to improve thermoregulation, but they are also linked with the development of Hashimoto's disease. In the brain, fetal cells could boost the caregiving skills of the mother and improve the nutrient transfer processes. Fetal cells are also associated with the stroma of brain tumors. Fetal microchimerism might predispose women to autoimmune diseases. This idea is supported by the fact that autoimmune diseases are more common in females. Research on fetal cells in the maternal body is important because it may answer questions about the pathophysiology of certain cancers and autoimmune diseases. It can also provide insights into graft rejection mechanisms and ways to overcome them. Microchimerism has been studied in several maternal diseases using different detection techniques [Table 1]. Many studies on microchimerism make the use of fluorescence in situ hybridization (FISH) for the detection of the Y chromosome. This is convenient because detecting male cells in a backdrop of female cells is easier.{Figure 1}{Table 1}
However, because of this, female fetal cell microchimerism is often overlooked. Many studies conducted on animal models use enhanced green fluorescent protein (EGFP) or vascular endothelial growth factor receptor 2 (VEGFR2)-luciferase (V-Luc) transgenic mice.
In this review, the outcomes of fetal microchimerism in the mother will be covered. It discusses the migration of fetal cells to the maternal circulation and the probable period during gestation when the migration occurs. It goes on to discuss the link between fetal cell microchimerism and the development of autoimmune diseases and cancer prognosis. Finally, it talks about the different organs inhabited by the cells and how they contribute to the functioning of those organs.
Migration of Fetal Cells during Pregnancy
After implantation, the primary syncytium (PS), formed from the fusion of trophectodermal cells, invades the decidua. The decidua is formed as a result of modifications in the endometrium during pregnancy.[4] The PS abrades the uterine blood capillaries and glands. Primary chorionic villi, which consist of outer syncytiotrophoblast and inner cytotrophoblast cells, are formed and later develop into a villous tree. The cytotrophoblast cells interact with the decidua to form the cytotrophoblast shell, which lies at the interface of the villi and the decidua. The primary villi develop into secondary and subsequently into tertiary villi. The cytotrophoblast cells later invade the decidua basalis. As a result, the placenta is formed, which is a composite tissue having both maternal and fetal origins.
In humans, the umbilical cord holds the blood vessels of the fetus, and maternal blood enters the placenta through trophoblast-lined remodeled spiral arteries.[7] In the placenta, maternal blood is situated in the intervillous space. Maternal and fetal circulation is separated by the placental barrier, which is comprised of syncytiotrophoblast. Three mechanisms have been proposed for fetal cell migration across the placenta [Figure 2].[8] First, a hemorrhage can occur in the placenta, which would lead to the migration of cells to the maternal circulation. Second, trophoblasts that line the maternal arteries can get expelled and enter the maternal circulation. Third, fetal cells adhere to endothelial cells lining the fetal capillary and migrate across the trophoblast layer.{Figure 2}
There is a high probability that fetal cells migrate to the maternal circulation and eventually to the maternal organs during the first trimester.[2] The study aims to estimate the time during a pregnancy when the migration takes place. Female wild-type (WT) mice were bred with male mice transgenic for EGFP. During pregnancy, EGFP + fetal cells were found in many maternal tissues and organs and their amount increased with the gestational period. Pregnant mice were euthanized on days 6, 13, and 19 of pregnancy. Posthysterectomy, the mice were either injected with streptozotocin (STZ) or a vehicle. Organs such as bone marrow, heart, lungs, kidneys, liver, and pancreas were dissected for detection of fetal cells.
Irrespective of the time of hysterectomies, only the bone marrow showed the presence of fetal cells. The cells were present in a mature form, like the HSCs of the mother. However, after the STZ-induced injury, fluorescent cells were found in damaged organs such as the liver, kidneys, and pancreas and not in the unaffected organs. The cells were in a differentiated state, thus suggesting a role in tissue repair. The study concluded that the migration of multipotent fetal cells begins soon after the implantation. After the delivery, the persistence of fetal cells lasts for a long period.[2]
Defects in the process of placenta formation are regarded as the underlying cause of preeclampsia.[9] Preeclampsia is a disorder that occurs during pregnancy and is identified by hypertension, organ failure, and proteinuria.[10] A study reported that fetal cell microchimerism occurred more frequently in cases with preeclampsia as compared to cases with healthy pregnancies.[11] They also detected higher amounts of microchimerism in women with preeclampsia.
Dysfunctional cellular migration through the placenta has been associated with preeclampsia.[12] Studies showing increased fetal erythrocytes in maternal circulation in preeclampsia deemed abrasions in the placenta as the cause of increased cell transfer.[13] In addition to fetal cells, an increase in cell-free fetal DNA has also been associated with preeclampsia.[14]
Prevalence and Long-term Persistence of Fetal Microchimerism
Although studies conducted to detect fetal microchimerism are not usually conducted in healthy women, studies where healthy women are utilized as controls show that fetal microchimerism is a common phenomenon.[15] It is proposed that feto-maternal trafficking occurs in all human pregnancies.[16] In a study, one-third of the healthy women had male fetal cells.[17] Whereas, three-fifth of the women with systemic sclerosis (SSc) harbored male fetal cells. In studies focusing on determining the prevalence of fetal microchimerism in cases with autoimmune diseases, it is reported that microchimerism is detected in healthy control subjects at a range of 0%–72% cases.[16]
After the delivery, the persistence of fetal cells lasts for a long period. A study reported the detection of DNA derived from microchimeric fetal cells in 70% of liver samples tested. The cells had persisted in the liver for 43 years postpregnancy.[18] A study conducted in 32 pregnant and 8 nonpregnant women reported the detection of male fetal cells in the blood samples of 17 pregnant women and 6 nonpregnant women.[19] In the pregnant women, male cells were either from current male fetuses or previous male pregnancies. In the nonpregnant women with prior male pregnancies, male fetal cells had persisted for periods as long as 27 years.
The persistence of microchimerism has also been studied in mice. A study was conducted to assess cell migration between the fetus and the mother.[20] For this purpose, syngeneic, allogeneic, and outbred pregnancies were studied. Blood was collected at different time points for the detection of EGFP-positive fetal cells using nested polymerase chain reaction (PCR). In syngeneic pregnancies, fetal cells were detected in maternal circulation 10 days after conception and their numbers remained constant thereafter. However, after the delivery, the fetal cells were cleared off, as no fetal cells were detected after birth. In allogeneic pregnancies, fetal cells were detected 10 days after conception and their numbers increased before declining prior to birth. Twenty-one days after birth, fetal cells persisted in 2 out of 5 mice. Forty-two days after birth, no fetal cells were detected. In outbred pregnancies, the prevalence of cell migration was low as compared to the first two cases. Fetal cells were first detected thirteen days after conception. Twenty-one days after birth, no fetal cells were detected. However, forty-two days after birth, persistent fetal cells were detected in 2 out of 5 mice. It was speculated that in allogeneic and outbred pregnancies, fetal cells persisted after birth because of the development of tolerance.[20]
Fetal Cell Microchimerism in Different Organs of the Mother
Once in circulation, fetal cells have access to the maternal organs. Male adult cardiomyocytes can be observed in female hearts.[21] A part of this male microchimerism can be credited as fetal cell microchimerism. Two female heart explants from idiopathic dilated cardiomyopathy patients were tested for the presence of male fetal cell microchimerism. Sex-determining region Y (SRY) gene was amplified by reverse transcription PCR (RT-PCR), and the male fetal cells were located using FISH. The mothers and their sons were human leukocyte antigen (HLA) compatible, which accounts for the absence of an immune reaction. The probability that the fetal cells could have led to cardiomyopathy is low because there was a substantial time interval between the last pregnancies and the appearance of the condition. Fetal cells were more likely protective, as tissue damage stimulates stem cell regeneration and differentiation.
Microchimerism has also been observed in the central nervous system (CNS). Male fetal cell microchimerism was assessed in brain samples of 59 diseased females.[22] The brain samples were obtained from both women with no signs of neurological disorders and from those with Alzheimer's disease (AD). RT-PCR was performed to detect the Y chromosome. Fetal cell microchimerism was detected at a higher rate in samples without any disorder than in the samples with AD. In addition, although not significantly, microchimerism was less in areas commonly damaged in AD. These results indicate that fetal cells and fetal DNA can pass through the blood–brain barrier and infiltrate different regions of the brain and stay there for years after pregnancy.[22]
Given the capability of microchimeric fetal cells to infiltrate the brain, an obvious question is regarding the capability of fetal cells to infiltrate the spinal cord of the mother.[23] WT female mice were mated with male mice transgenic for green fluorescent protein (GFP). As a result, the fetal cells expressed GFP and were detected using fluorescent microscopy and by the anti-GFP antibody. Fetal cells were detected in the spinal cord and seemed to have differentiated into neuronal cell types by expressing neuronal nuclear protein (NeuN). This indicated that the cells were able to pass the blood–spinal cord barrier. Although there was a low abundance of these cells in the spinal cord, there was a positive correlation between the number of pregnancies and the number of fetal cells.
Immunological Outcomes of Fetal Microchimerism
The fetus is recognized as semi-allogeneic by the maternal immune system because of the expression of paternal genes such as the major histocompatibility complex MHC Class I and II molecules and products of the Y chromosome in the case of a male fetus.[24] Despite the potentially foreign nature of the fetus, in most cases, the fetus is not rejected by the maternal system. During pregnancy, the mother's immune system is somewhat suppressed and fetal cells migrate to the maternal circulation. It is speculated that microchimerism during pregnancy occurs to establish tolerance toward the fetus in the mother.[24]
Early during pregnancy, fetal cells enter the maternal liver through the portal circulation and they present their alloantigens to the maternal T-cells.[25],[26] It is hypothesized that the fetal tolerance develops as a result of the inhibition or absence of signals from co-stimulatory molecules, which are essential for a T-cell response. The immune tolerance, thus developed, expands and a “global peripheral tolerance” is developed.[24]
A perturbation in the tolerance due to irregular microchimerism can lead to the induction of autoimmune conditions. Fetal cells that differentiate into antigen-presenting cells (APCs) can contribute to the breakdown of tolerance.[19],[24] It is speculated that high levels of distinctiveness in antigen processing and the MHC molecules of the fetal cells can lead to the breakdown.[24] Furthermore, the extent to which the fetal cells are allogeneic as compared to the maternal cells could lead to a malfunction in the developed tolerance. After the loss of tolerance, fetal APCs and maternal APCs can present fetus-specific antigens to the maternal T-cells, this would lead to the activation of T-cells, and a subsequent cytokine production would activate cells such as macrophages, B-cells, natural killer cells, and cytotoxic T-cells.[27],[28],[29] This can lead to an autoimmune condition.[30]
Another mechanism for autoimmune condition development involves fetal T-cells. A study demonstrated that common lymphoid progenitor cells of fetal origin enter the maternal thymus.[31] In the thymus, the cells undergo thymic development and form mature T-cells of fetal origin. Fetal T-cells have been discovered in women with SSc and healthy women. In the thymus, the cells undergo positive and negative selection. It is thought that fetal T-cells in healthy women undergo positive selection and are not reactive toward the maternal system. On the other hand, fetal T-cells that are reactive toward maternal antigens are removed through negative selection. It is theorized that if such fetal T-cells are not removed, an autoimmune condition can arise.[32]
Several genetic factors are involved in the development of autoimmune diseases. Polymorphism in the HLA Class II genes is one of the factors. HLA-DRβ1 alleles code for a sequence, D-Aspartic acid (Asp) E-Glutamic acid (Glu) R-Arginine (Arg)A-Alanine (Ala) A-Alanine (Ala)(DERAA). Normally, DERAA protects an individual against rheumatoid arthritis (RA). This is because, in DERAA-positive individuals, autoreactive T-cells are eradicated during development. However, in a study, it was found that in females, without DERAA, bearing fetuses with DERAA, the protective function was lost.[33] Instead, DERAA-positive fetus made the mother more susceptible to RA. It was speculated that T-cells specific toward DERAA peptide were activated on exposure to the peptide displayed on fetal microchimeric cells and immune response was initiated. This immune response in the long term led to the development of RA.[33]
Evidence of microchimerism was also assessed in Hashimoto's thyroiditis (HT).[34] Seventeen patients with HT were compared with 25 patients with goiter. Forty-seven percent of HT patients exhibited the presence of the Y chromosome as against just one patient from the control group. These results were obtained on PCR amplification of the SRY gene of the Y chromosome in thyroid tissue samples. It was suggested that male microchimeric cells could cause dysregulation of regulatory T-cells, thus allowing uncontrolled activity of self-reactive immune cells.
Microchimerism was detected in healthy controls and systemic lupus patients at the same rate.[35] Microchimerism was more evident in renal lupus and less evident in cutaneous lupus. There was a positive correlation between the amount of microchimerism and the number of abortions.
The link between fetal microchimerism in different organs and SSc was assessed.[36] In all the tissue samples assessed, the spleen had the highest number of microchimeric male cells. Cells were also present in the lymph nodes and other organs. Such results were obtained because the spleen and lymph nodes screen the blood and trap the fetal cells. It was speculated that some amount of tolerance is developed in the female body for the microchimeric cells. Although fetal cells were detected in organs typically affected by SSc, essentially there may not be causation.
A study reported that male microchimerism was observed in the peripheral blood of both healthy women and women affected with Sjögren's syndrome (SS).[37] However, in the salivary glands, it was observed that male microchimerism was more common in patients with SS. It was speculated that the penetrating fetal cells damaged the salivary gland. Primary biliary cirrhosis, however, was not found to be associated with fetal microchimerism.[38]
Although results show that microchimerism is evident in females with autoimmune diseases, results also show that microchimerism is evident in most women with no signs of any immunological outcome. This indicates that there is something more at play in addition to fetal microchimerism in the development of autoimmune diseases. The development of autoimmune diseases because of fetal microchimerism is an exception and not a rule.
Involvement of Fetal Cells in Cancer Prognosis in the Maternal Organs
Gestation-coupled breast cancer was induced in Mouse Mammary Tumor Virus-Harvey rat sarcoma viral oncogene (MMTV-H-Ras) transgenic female mice.[39] Female mice were mated with either WT male mice or V-Luc male mice, and a total of ten mice developed tumors (nine developed breast tumors and one developed a salivary tumor).
Liver samples from the same respective females were utilized as control. FISH for the Y chromosome revealed the presence of fetal cells in all the breast cancer samples and only two of the eight liver samples. Salivary gland tumors showed no signs of fetal cells. The number of fetal cells was more in breast cancer samples when compared to the liver samples. High-grade tumors had a higher load of fetal cells. Females with V-Luc fetuses showed no endothelial cells in the tumor sites. Phenotypic analysis revealed that the fetal cells possessed an epithelial phenotype because of the display of cytokeratin. Similar studies on gestational breast cancer samples from humans showed that cells displayed both vimentin and cytokeratin.[40] It was hypothesized that the fetal cells underwent mesenchymal–epithelial transition upon entering the tumor sites and participated in the tumor microenvironment. The epithelial background of the breast tumor seemed to induce the adoption of a similar phenotype in fetal cells.
The same was observed for brain tumors. Two common brain tumors were selected for this purpose, meningioma, and glioblastoma. Meningioma is a sex hormone-reactive low-grade cancer more common in females, whereas glioblastoma is a sex hormone-independent high-grade cancer more common in males. Quantitative PCR for the Y chromosome-specific gene DSY14 and FISH to detect the intact cells with XY genotype were conducted.[41] The incidence of fetal cell microchimerism was higher in females diagnosed with glioblastoma as compared to females diagnosed with meningioma.
The larger amounts of microchimerism in glioblastoma samples as compared to that in meningioma samples could be due to the higher tendency of cells to assemble in glioblastomas and lower tendency to assemble in meningiomas, or the presence of fetal cells can predispose one to glioblastomas. Fetal cells can either be present in the tissue before the tumor develops or actively infiltrate after tumor formation. The low incidence of intact cells in both the tumors suggests that the fetal cells act as part of the tumor microenvironment and not the cancerous growth. Conclusive evidence is required to determine whether fetal microchimerism is involved in carcinogenesis or repair processes.
A study conducted to determine the association between fetal microchimerism and papillary thyroid cancer (PTC) focused on the detection of male fetal cells in cancerous tissue and normal tissue from women.[42] Male fetal cells were detected using PCR and FISH. Samples from almost half of the PTC patients with male pregnancies exhibited the presence of male DNA. Male fetal cells were more prevalent in cancerous tissue as compared to the healthy tissue from the same respective patients. Male fetal cells positive for CD45 were detected only in the cancerous tissue and not in the normal tissue and they did not express MHC Class II molecules. As a result of their expression, they were likely macrophages or natural killer cells which would help in eliminating the cancer cells. Male fetal cells positive for thyroglobulin (epithelial maker) were detected in both the cancerous tissue and healthy tissue and they did not express MHC Class II molecules. As a result, they were more likely participating in repair of the damaged thyroid gland.
In another study, male fetal cells were detected only in women with cervical cancer diagnosis and previous male pregnancies.[43] Phenotyping revealed that the cells were either CD45 positive or cytokeratin positive. CD45-positive fetal cells were probably involved in the elimination of cancer cells. Whereas, cytokeratin-positive cells indicate an epithelial lineage. It was speculated that fetal stem cells differentiated into epithelial cells because of the epithelial background of the cervix. These cells were either called upon for repair of the damaged tissue after carcinogenesis or carcinogenesis was the result of persistence of fetal microchimerism.
The contribution of fetal microchimerism as a protective factor or a vulnerability factor in cancer prognosis in the mother seems to depend upon the cell lineage that the fetal cells differentiate into.[32] In thyroid and cervical cancers, CD45-positive cells that differentiated into a hematopoietic lineage were associated with the elimination of cancer cells.[42],[43] In breast, thyroid, and cervical cancers, cells from mesenchymal lineage (cells expressing vimentin) and epithelial lineage (cells expressing cytokeratin and thyroglobulin) were found in the microenvironment of the tumor.[39],[40],[42],[43] These cells could either contribute to the repair of damaged tissue or could be associated with carcinogenesis. Fetal cells that differentiate into endothelial cells could help in cancer progression by aiding in the process of neoangiogenesis.[44]
Involvement of Fetal Cells in Tissue Repair at Maternal Injury Sites
Tissue damage triggers the proliferation of progenitor cells to compensate for or repair the damage. Inflammation-induced neoangiogenesis is a prominent process in this response. A study aimed to assess the contribution of progenitor cells of fetal origin to neoangiogenesis at inflamed sites in pregnant mice.[45] Oxazolone was used to induce contact hypersensitivity reaction on the right ears of WT female mice bearing EGFP-positive fetuses or V-Luc-positive fetuses. Amplification of the EGFP DNA revealed a higher load of fetal cell populations in the inflamed right ear when compared to the noninflamed left ear. Double labeling was employed to assess the phenotype of the cells.
Females with V-Luc fetuses exhibited a larger Luc activity in the inflamed ear, and the cells were marked with (cluster of differentiation) CD31 and VEGFR2, which suggested an endothelial progenitor cell identity. Fetal cells with CD45, which is a leukocyte marker, were also detected. The presence of blood vessels entirely made of fetal cells indicated that fetal cells contribute to angiogenesis in the mother.
It is established that fetal cells are present in the circulation of the mother during pregnancy and after pregnancy.[46] EGFP male mice were mated with WT females. The females were given ethanol to develop liver injury over a period, and gentamicin was given to induce kidney injury. EGFP-positive fetal cells were observed in the maternal circulation postpregnancy, and in addition to this, they were also observed in the bone marrow and damaged liver and kidneys. The fetal cells were found to have adopted hepatocyte phenotype or tubular cell phenotype after entering the liver and the kidneys, respectively. It was hypothesized that the cells probably did so to contribute to the repair mechanisms.
Similar results were obtained in a study on humans diagnosed with lung injury. Women who had had male pregnancies and were diagnosed with some form of lung cancer 10–20 years postpregnancy were selected for the study. Lung and thymus tissue samples were taken, and FISH was conducted for the detection of the Y chromosome.[47] Male fetal cells were present in the tissue samples from the bone, the marrow, the lungs, and the thymus gland. The load of the fetal cells was seven times higher than that in the marrow and two times higher than that in the bone. The cell load was also found to be higher in damaged tissue as compared to normal tissue.
The role played by fetal cells in tissue repair of the mother has been evaluated in many studies.[20],[46],[47] The proposed mechanism is that chemokines produced by injured tissues attract fetal cells in the maternal system and signals lead to their differentiation into cell types that contribute to the repair process.[2],[16] It is also theorized that tissues with chronic damage can attract microchimeric cells.[46],[47] It is also suggested that injured tissues facilitate the permanence of fetal cells. Based on what has been observed in cancer, mesenchymal and epithelial cell lineages can be recruited to the damaged sites to contribute to the repair process.
Fetal microchimerism can have many outcomes in the mother or their presence can be inconsequential. The ascertainment of whether fetal microchimerism would lead to tissue repair, an autoimmune condition or carcinogenesis seems to depend on certain factors. Majorly, it appears to depend upon the fetal cell type under consideration and its differentiation fate. As discussed before, cells of mesenchymal and epithelial lineages can help in repair and cells of hematopoietic lineage can help in cancer cell eradication. However, the persistence of fetal cells can also aid in carcinogenesis. On the other hand, cells that help in angiogenesis can help in tissue repair process or help in cancer progression. Fetal T-cells reactive toward maternal antigens that are not removed can also lead to an autoimmune condition. Finally, the infrequent breakdown of tolerance toward the fetus can lead to the development of an autoimmune condition.
Conclusion
Cell migration occurs between the mother and the fetus during pregnancy. Migration of multipotent fetal cells begins soon after the implantation. These cells contribute to microchimerism in the mother. Increased cell migration is associated with preeclampsia. Studies have shown that fetal microchimerism is a common phenomenon in all human pregnancies. These cells have access to maternal organs including the CNS, bone marrow, heart, kidney, liver, and several glands. As the fetal cells are hemizygous, they are partially foreign in the female body. After the delivery, the persistence of fetal cells lasts for a long period. As the fetus is semi-allogeneic, a tolerance is developed by the maternal system during pregnancy. Over a period, in some individuals, these cells can elicit an immune response and initiate autoimmune diseases such as Hashimoto's disease, SSc, systemic lupus, SS, and RA. However, seeing as fetal microchimerism is common in women without any immunological disease, it is unlikely that fetal cells are the sole cause of autoimmune diseases. The stroma of tumors in maternal tissues exhibited the presence of fetal cells, where they are thought to have prognostic significance. Contribution to the prognosis of maternal cancers can be determined by the fetal cell phenotype. Furthermore, fetal cells have been detected at injury sites contributing to the repair and regeneration of maternal tissues. Research on fetal cell microchimerism has come a long way due to the development of techniques such as PCR, FISH, and immunohistochemistry. However, major research employs the detection of Y chromosome microchimerism or male fetal cells, and such studies overlook the implications of female fetal cell microchimerism in the mother. Studying microchimerism is important as it leads to changes in the maternal body during and after pregnancy. These changes can be harmful or beneficial but are significant and vary from woman to woman. In the future, studies regarding the homing process of these cells should be conducted to understand the subsequent repair and damage processes.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
| 1 | Knippen MA. Microchimerism: sharing genes in illness and in health. ISRN Nurs 2011; 2011:893819. |
| 2 | Sunami R, Komuro M, Yuminamochi T, Hoshi K, Hirata S. Fetal cell microchimerism develops through the migration of fetus-derived cells to the maternal organs early after implantation. J Reprod Immunol 2010; 84:117-23. |
| 3 | Boddy AM, Fortunato A, Wilson Sayres M, Aktipis A. Fetal microchimerism and maternal health: a review and evolutionary analysis of cooperation and conflict beyond the womb. Bioessays 2015; 37:1106-18. |
| 4 | Turco MY, Moffett A. Development of the human placenta. Development 2019; 146: dev163428. |
| 5 | Anatomy and the human body [Internet]. Servier.com. Available from: https://smart.servier.com/category/anatomy-and-the-human-body/. [Last accessed on 2021 May 25]. |
| 6 | Sidiropoulos K, Viteri G, Sevilla C, Jupe S, Webber M, Orlic-Milacic M, et al. Reactome enhanced pathway visualization. Bioinformatics 2017; 33:3461-7. |
| 7 | Georgiades P, Ferguson-Smith AC, Burton GJ. Comparative Developmental Anatomy of the Murine and Human Definitive Placentae. Placenta 2002; 23:3-19. |
| 8 | Dawe GS, Tan XW, Xiao Z-C. Cell migration from baby to mother. Cell Adh Migr 2007; 1:19-27. |
| 9 | Johansen M, Redman CW, Wilkins T, Sargent IL. Trophoblast deportation in human pregnancy--its relevance for pre-eclampsia. Placenta 1999; 20:531-9. |
| 10 | Hahn S, Hasler P, Vokalova L, van Breda SV, Than NG, Hoesli IM, et al. Feto-maternal microchimerism: The pre-eclampsia conundrum. Front Immunol 2019; 10:659. |
| 11 | Gammill HS, Aydelotte TM, Guthrie KA, Nkwopara EC, Nelson JL. Cellular fetal microchimerism in preeclampsia. Hypertension 2013; 62:1062-7. |
| 12 | Holzgreve W. Disturbed feto-maternal cell traffic in preeclampsia. Obstet Gynecol 1998; 91:669-72. |
| 13 | Al-Mufti R, Hambley H, Albaiges G, Lees C, Nicolaides KH. Increased fetal erythroblasts in women who subsequently develop pre-eclampsia. Hum Reprod 2000; 15:1624-8. |
| 14 | Lo YM, Leung TN, Tein MS, Sargent IL, Zhang J, Lau TK, et al. Quantitative abnormalities of fetal DNA in maternal serum in preeclampsia. Clin Chem 1999; 45:184-8. |
| 15 | O'Donoghue K, Chan J, de la Fuente J, Kennea N, Sandison A, Anderson JR, et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 2004; 364:179-82. |
| 16 | O'Donoghue K. Fetal microchimerism and maternal health during and after pregnancy. Obstet Med 2008; 1:56-64. |
| 17 | Evans PC, Lambert N, Maloney S, Furst DE, Moore JM, Nelson JL. Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 1999; 93:2033-7. |
| 18 | Tanaka A, Lindor K, Gish R, Batts K, Shiratori Y, Omata M, et al. Fetal microchimerism alone does not contribute to the induction of primary biliary cirrhosis. Hepatology 1999; 30:833-8. |
| 19 | Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A 1996; 93:705-8. |
| 20 | Vernochet C, Caucheteux SM, Kanellopoulos-Langevin C. Bi-directional cell trafficking between mother and fetus in mouse placenta. Placenta 2007; 28:639-49. |
| 21 | Bayes-Genis A, Bellosillo B, de la Calle O, Salido M, Roura S, Ristol FS, et al. Identification of male cardiomyocytes of extracardiac origin in the hearts of women with male progeny: male fetal cell microchimerism of the heart. J Heart Lung Transplant 2005; 24:2179-83. |
| 22 | Chan WFN, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, Nelson JL. Male microchimerism in the human female brain. PLoS One 2012; 7: e45592. |
| 23 | Zhang G, Zhao Y, Li X-M, Kong J. Fetal cell microchimerism in the maternal mouse spinal cord. Neurosci Bull 2014; 30:81-9. |
| 24 | Tanaka A, Lindor K, Ansari A, Gershwin M. Fetal microchimerism in the mother: Immunologic implications. Liver Transpl 2000; 6:138-43. |
| 25 | Koyamada N, Ohteki T, Abo T, Fukumori T, Ohkouchi N, Satomi S, et al. Induction of specific tolerance by hepatic double-negative CD4-8-αβ T cells of mice immunized with allogeneic cells via the portal vein in vitro. Cell Immunol 1993; 149:107-16. |
| 26 | Jin T, Sugiura K, Ishikawa J, Lee S, Morita H, Nagahama T, et al. Persistent tolerance induced after portal venous injection of allogeneic cells plus cyclophosphamide treatment. Immunobiology 1999; 200:215-26. |
| 27 | Sayegh MH, Watschinger B, Carpenter CB. Mechanisms of t cell recognition of alloantigen: The role of peptides. Transplantation 1994; 57:1295–302. |
| 28 | Parker KE, Dalchau R, Fowler VJ, Priestley CA, Carter CA, Fabre JW. Stimulation of cd4+ t lymphocytes by allogeneic mhc peptides presented on autologous antigen-presenting cells: Evidence of the indirect pathway of allorecognition in some strain combinations. Transplantation 1992; 53:918-24. |
| 29 | Watschinger B, Gallon L, Carpenter CB, Sayegh MH. Mechanisms of allo-recognition. Recognition by in vivo-primed T cells of specific major histocompatibility complex polymorphisms presented as peptides by responder antigen-presenting cells. Transplantation 1994; 57:572-6. |
| 30 | Nelson JL. Microchimerism: incidental byproduct of pregnancy or active participant in human health? Trends Mol Med 2002; 8:109-13. |
| 31 | Khosrotehrani K, Leduc M, Bachy V, Huu SN, Oster M, Abbas A, et al. Pregnancy allows the transfer and differentiation of fetal lymphoid progenitors into functional T and B cells in mothers. J Immunol 2008; 180:3613.2-3613. |
| 32 | Fugazzola L, Cirello V, Beck-Peccoz P. Fetal microchimerism as an explanation of disease. Nat Rev Endocrinol 2011; 7:89-97. |
| 33 | Kanaan SB, Sensoy O, Yan Z, Gadi VK, Richardson ML, Nelson JL. Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism. Proc Natl Acad Sci U S A 2019; 116:19600-8. |
| 34 | Klintschar M, Schwaiger P, Mannweiler S, Regauer S, Kleiber M. Evidence of fetal microchimerism in Hashimoto's thyroiditis. J Clin Endocrinol Metab 2001; 86:2494-8. |
| 35 | Abdulaziez O, Abdulmaksud S, Elbakry S, Shawky S, Mekawy M, Salah K. Y chromosome microchimerism in patients with systemic lupus erythematosus. Egypt Rheumatol 2012; 34:27-33. |
| 36 | Johnson KL, Nelson JL, Furst DE, McSweeney PA, Roberts DJ, Zhen DK, et al. Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis Rheum 2001; 44:1848-54. |
| 37 | Endo Y, Negishi I, Ishikawa O. Possible contribution of microchimerism to the pathogenesis of Sjögren's syndrome. Rheumatology (Oxford) 2002; 41:490-5. |
| 38 | Corpechot C, Barbu V, Chazouillères O, Poupon R. Fetal microchimerism in primary biliary cirrhosis. J Hepatol 2000; 33:696-700. |
| 39 | Dubernard G, Oster M, Chareyre F, Antoine M, Rouzier R, Uzan S, et al. Increased fetal cell microchimerism in high grade breast carcinomas occurring during pregnancy. Int J Cancer 2009; 124:1054-9. |
| 40 | Dubernard G, Aractingi S, Oster M, Rouzier R, Mathieu M-C, Uzan S, et al. Breast cancer stroma frequently recruits fetal derived cells during pregnancy. Breast Cancer Res 2008; 10: R14. |
| 41 | Broestl L, Rubin JB, Dahiya S. Fetal microchimerism in human brain tumors: Fetal microchimerism in human brain tumors. Brain Pathol 2018; 28:484-94. |
| 42 | Cirello V, Recalcati MP, Muzza M, Rossi S, Perrino M, Vicentini L, et al. Fetal cell microchimerism in papillary thyroid cancer: a possible role in tumor damage and tissue repair. Cancer Res 2008; 68:8482-8. |
| 43 | Cha D, Khosrotehrani K, Kim Y, Stroh H, Bianchi DW, Johnson KL. Cervical cancer and microchimerism. Obstet Gynecol 2003; 102:774-81. |
| 44 | Nguyen Huu S, Oster M, Avril M-F, Boitier F, Mortier L, Richard M-A, et al. Fetal microchimeric cells participate in tumour angiogenesis in melanomas occurring during pregnancy. Am J Pathol 2009; 174:630-7. |
| 45 | Huu SN, Oster M, Uzan S, Chareyre F, Aractingi S, Khosrotehrani K. Maternal neoangiogenesis during pregnancy partly derives from fetal endothelial progenitor cells. Proc Natl Acad Sci U S A 2007;104: 1871-76. |
| 46 | Wang Y, Iwatani H, Ito T, Horimoto N, Yamato M, Matsui I, et al. Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. Biochem Biophys Res Commun 2004; 325:961-7. |
| 47 | O'Donoghue K, Sultan HA, Al-Allaf FA, Anderson JR, Wyatt-Ashmead J, Fisk NM. Microchimeric fetal cells cluster at sites of tissue injury in lung decades after pregnancy. Reprod Biomed Online 2008; 16:382-90. |
|
