Are fetal microchimerism and circulating fetal extracellular vesicles important links between spontaneous preterm delivery and maternal cardiovascular disease risk?

Trafficking and persistence of fetal microchimeric cells (fMCs) and circulating extracellular vesicles (EVs) have been observed in animals and humans, but their consequences in the maternal body and their mechanistic contributions to maternal physiology and pathophysiology are not yet fully defined. Fetal cells and EVs may help remodel maternal organs after pregnancy-associated changes, but the cell types and EV cargos reaching the mother in preterm pregnancies after exposure to various risk factors can be distinct from term pregnancies. As preterm delivery-associated maternal complications are rising, revisiting this topic and formulating scientific questions for future research to reduce the risk of maternal morbidities are timely. Epidemiological studies report maternal cardiovascular risk as one of the major complications after preterm delivery. This paper suggests a potential link between fMCs and circulating EVs and adverse maternal cardiovascular outcomes post-pregnancies, the underlying mechanisms, consequences, and methods for and how this link might be assessed.

Genetics of Sex Differences in Immunity.

Women have a stronger immune response and a higher frequency of most autoimmune diseases than men. While much of the difference between men and women is due to the effect of gonadal hormones, genetic differences play a major role in the difference between the immune response and disease frequencies in women and men. Here, we focus on the immune differences between the sexes that are not downstream of the gonadal hormones. These differences include the gene content of the sex chromosomes, the inactivation of chromosome X in women, the consequences of non-random X inactivation and escape from inactivation, and the states that are uniquely met by the immune system of women-pregnancy, birth, and breast feeding. While these female-specific states are temporary and involve gonadal hormonal changes, they may leave a long-lasting footprint on the health of women, for example, by fetal cells that remain in the mother's body for decades. We also briefly discuss the immune phenotype of congenital sex chromosomal aberrations and experimental models that enable hormonal and the non-hormonal effects of the sex chromosomes to be disentangled. The increasing human life expectancy lengthens the period during which gonadal hormones levels are reduced in both sexes. A better understanding of the non-hormonal effects of sex chromosomes thus becomes more important for improving the life quality during that period.

Y-chromosome in the olfactory neuroepithelium as a potential biomarker of depression in women with male offspring: an exploratory study.

The persistence of fetal cells in the mother (fetal microchimerism (FMc)) has been described in maternal tissues essential to the newborn. FMc is associated with several diseases that start or worsen in pregnancy or postpartum. This exploratory study reports-for the first time-the presence of FMc in the olfactory neuroepithelium (ON) of both healthy and depressed women with male offspring. However, depressed women had fewer microchimeric cells (digital PCR). The existence of FMc in the ON could facilitate mother-child bonding. These findings open new pathways to study FMc in the ON, female depression, and mother-child bonding.

Markers of placental function correlate with prevalence and quantity of nucleated fetal cells in maternal circulation in normotensive term pregnancies.

INTRODUCTION: Transplacental fetal cell transfer results in the engraftment of fetal-origin cells in the pregnant woman's body, a phenomenon termed fetal microchimerism. Increased fetal microchimerism measured decades postpartum is implicated in maternal inflammatory disease. Understanding which factors cause increased fetal microchimerism is therefore important. During pregnancy, circulating fetal microchimerism and placental dysfunction increase with increasing gestational age, particularly towards term. Placental dysfunction is reflected by changes in circulating placenta-associated markers, specifically placental growth factor (PlGF), decreased by several 100 pg/mL, soluble fms-like tyrosine kinase-1 (sFlt-1), increased by several 1000 pg/mL, and the sFlt-1/PlGF ratio, increased by several 10 (pg/mL)/(pg/mL). We investigated whether such alterations in placenta-associated markers correlate with an increase in circulating fetal-origin cells. MATERIAL AND METHODS: We included 118 normotensive, clinically uncomplicated pregnancies (gestational age 37+1 up to 42+2 weeks' gestation) pre-delivery. PlGF and sFlt-1 (pg/mL) were measured by Elecsys® Immunoassays. We extracted DNA from maternal and fetal samples and genotyped four human leukocyte antigen loci and 17 other autosomal loci. Paternally inherited, unique fetal alleles served as polymerase chain reaction (PCR) targets for detecting fetal-origin cells in maternal buffy coat. Fetal-origin cell prevalence was assessed by logistic regression, and quantity by negative binomial regression. Statistical exposures included gestational age (weeks), PlGF (100 pg/mL), sFlt-1 (1000 pg/mL) and the sFlt-1/PlGF ratio (10 (pg/mL)/(pg/mL)). Regression models were adjusted for clinical confounders and PCR-related competing exposures. RESULTS: Gestational age was positively correlated with fetal-origin cell quantity (DRR = 2.2, P = 0.003) and PlGF was negatively correlated with fetal-origin cell prevalence (odds ratio [OR]100 = 0.6, P = 0.003) and quantity (DRR100 = 0.7, P = 0.001). The sFlt-1 and the sFlt-1/PlGF ratios were positively correlated with fetal-origin cell prevalence (OR1000 = 1.3, P = 0.014 and OR10 = 1.2, P = 0.038, respectively), but not quantity (DRR1000 = 1.1, P = 0.600; DRR10 = 1.1, P = 0.112, respectively). CONCLUSIONS: Our results suggest that placental dysfunction as evidenced by placenta-associated marker changes, may increase fetal cell transfer. The magnitudes of change tested were based on ranges in PlGF, sFlt-1 and the sFlt-1/PlGF ratio previously demonstrated in pregnancies near and post-term, lending clinical significance to our findings. Our results were statistically significant after adjusting for confounders including gestational age, supporting our novel hypothesis that underlying placental dysfunction potentially is a driver of increased fetal microchimerism.

Pregnancy, postpartum and parity: Resilience and vulnerability in brain health and disease.

Risk and resilience in brain health and disease can be influenced by a variety of factors. While there is a growing appreciation to consider sex as one of these factors, far less attention has been paid to sex-specific variables that may differentially impact females such as pregnancy and reproductive history. In this review, we focus on nervous system disorders which show a female bias and for which there is data from basic research and clinical studies pointing to modification in disease risk and progression during pregnancy, postpartum and/or as a result of parity: multiple sclerosis (MS), depression, stroke, and Alzheimer's disease (AD). In doing so, we join others (Shors, 2016; Galea et al., 2018a) in aiming to illustrate the importance of looking beyond sex in neuroscience research.

Male microchimerism in peripheral blood from women with multiple sclerosis in Isfahan Province.

Multiple sclerosis (MS) is referred to as an organ-specific T-cell-mediated autoimmune disease of the central nervous system (CNS). Different genetic and environmental factors increase the risk of developing MS. In recent years, microchimerism (Mc) has been widely studied in autoimmune diseases, although the exact role of this phenomenon in human health is not known well. Microchimerism is the low level presence of DNA or cells from one individual into the tissue or circulation of another individual. In the current study, we evaluated the association of fetal microchimerism (FMc) with MS in Isfahan province. In this study, we enrolled 68 women in four groups. Two groups were MS patients with or without a pregnancy for a son, and the other two groups were MS-negative patients with or without a pregnancy for a son. The presence of the male genome assessed and compared in these groups. Four millilitres of peripheral blood were collected from all subjects in the tube containing EDTA and DNA was extracted. Real-time PCR assay was used for the DAZ (deleted in azoospermia) region Yq 11.23 as a marker for male microchimerism in all subjects. Our results showed that the percentage of DAZ (male genome)-positive women was significantly higher in MS-positive women given birth to a son in comparison with the other three groups. Our results also revealed no significant correlation between the percentage of DAZ-positive women and Expanded Disability Status Scale (EDSS) score and age of onset in the patients' group. For future studies, we suggest enrolling subjects who MS diagnosis occurred before and after pregnancy with a son. Comparing FMc in these two groups might provide a better understanding of the possible role of FMc in later development of MS.

Immunologic benefit of maternal donors in pediatric living donor liver transplantation.

PURPOSE OF REVIEW: Long-term follow-up has suggested that pediatric LDLT may have superior outcomes compared to deceased donor recipients. In this review, we describe the subset of LDLT recipients with maternal donors that have lower reported rates of rejection and improved allograft survival. RECENT FINDINGS: Pediatric LDLT recipients, particularly those with a primary diagnosis of biliary atresia who receive grafts from their mothers, have been reported to have lower rates of acute cellular rejection post-transplant and graft failure. Maternal-fetal microchimerism and the persistence of regulatory T cells may be related to improved outcomes observed in recipients with maternal donors. Further, recent studies have shown that up to 60% of pediatric LDLT recipients can undergo intentional withdrawal of immunosuppression and achieve long-term operational tolerance. The impact of graft type on operational tolerance has not been thoroughly investigated; however, investigation of tolerant pediatric LDLT patients with maternal donors may provide key insights into the mechanisms of immune tolerance. SUMMARY: While excellent outcomes can be achieved in pediatric LDLT, there is still a measurable decrease in graft and patient survival over time post-transplant. Recipients of maternal donor liver transplants are a subset of patients who may be advantaged toward improved outcomes by means of immune tolerance.

Fetal-origin cells in maternal circulation correlate with placental dysfunction, fetal sex, and severe hypertension during pregnancy.

Fetal microchimerism (FMc) arises when fetal cells enter maternal circulation, potentially persisting for decades. Increased FMc is associated with fetal growth restriction, preeclampsia, and anti-angiogenic shift in placenta-associated proteins in diabetic and normotensive term pregnancies. The two-stage model of preeclampsia postulates that placental dysfunction causes such shift in placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLt-1), triggering maternal vascular inflammation and endothelial dysfunction. We investigated whether anti-angiogenic shift, fetal sex, fetal growth restriction, and severe maternal hypertension correlate with FMc in hypertensive disorders of pregnancy with new-onset features (n = 125). Maternal blood was drawn pre-delivery at > 25 weeks' gestation. FMc was detected by quantitative polymerase chain reaction targeting paternally inherited unique fetal alleles. PlGF and sFlt-1 were measured by immunoassay. We estimated odds ratios (ORs) by logistic regression and detection rate ratios (DRRs) by negative binomial regression. PlGF correlated negatively with FMc quantity (DRR = 0.2, p = 0.005) and female fetal sex correlated positively with FMc prevalence (OR = 5.0, p < 0.001) and quantity (DRR = 4.5, p < 0.001). Fetal growth restriction no longer correlated with increased FMc quantity after adjustment for correlates of placental dysfunction (DRR = 1.5, p = 0.272), whereas severe hypertension remained correlated with both FMc measures (OR = 5.5, p = 0.006; DRR = 6.3, p = 0.001). Our findings suggest that increased FMc is independently associated with both stages of the two-stage preeclampsia model. The association with female fetal sex has implications for microchimerism detection methodology. Future studies should target both male and female-origin FMc and focus on clarifying which placental mechanisms impact fetal cell transfer and how FMc impacts the maternal vasculature.

Fetal microchimerism cells suppress arthritis progression by inducing CD14+ IL-10+ cells in pregnant experimental mice.

BACKGROUND: Fetal microchimerism occurs in the mother after a pregnancy. To investigate the role of fetal microchimerism cells (FMCs) in rheumatoid arthritis, we analyzed the population of fetal cells in pregnant experimental arthritis mice. METHODS: We used EGFP+ fetuses, which were mated with either healthy female mice or CIA mice, and male C57BL/6J-Tg (Pgk1-EGFP)03Narl mice, to detect the population of FMCs in maternal circulation. The disease progression was determined by measuring the clinical score and histological stains during pregnancy. The fetal cells have been analyzed if expressing EGFP, CD45, and Scal by flow cytometry. We also detected the expression of CD14+ IL-10+ cells in vivo and in vitro. RESULTS: Our data showed that the pregnancy ameliorated the arthritis progression of CIA mice. The IHC stains showed the CD45 -Sca-1+ EGFP+ FMCs were expressed in the bone marrow and peripheral blood mononuclear cells (PBMC) at 14 gestation days. However, Treg and Tc cell populations showed no significant change in the bone marrow. The data showed the H2Kb + fetal cells induced CD14+ IL10+ cell populations increased in the bone marrow in vitro and in vivo. CONCLUSION: Our investigations demonstrated that the FMCs protected the CIA mice from cartilage damage and triggered an immunosuppressive response in them by increasing the number of CD14+ IL10+ cells. In conclusion, the FMCs could potentially exhibit protective properties within the context of inflammatory arthritis that arises during pregnancy.

Characterization of fetal microchimeric immune cells in mouse maternal hearts during physiologic and pathologic pregnancies.

Introduction: During pregnancy, fetal cells can be incorporated into maternal tissues (fetal microchimerism), where they can persist postpartum. Whether these fetal cells are beneficial or detrimental to maternal health is unknown. This study aimed to characterize fetal microchimeric immune cells in the maternal heart during pregnancy and postpartum, and to identify differences in these fetal microchimeric subpopulations between normal and pregnancies complicated by spontaneous preterm induced by ascending infection. Methods: A Cre reporter mouse model, which when mated with wild-type C57BL/6J females resulted in cells and tissues of progeny expressing red fluorescent protein tandem dimer Tomato (mT+), was used to detect fetal microchimeric cells. On embryonic day (E)15, 104 colony-forming units (CFU) E. coli was administered intravaginally to mimic ascending infection, with delivery on or before E18.5 considered as preterm delivery. A subset of pregnant mice was sacrificed at E16 and postpartum day 28 to harvest maternal hearts. Heart tissues were processed for immunofluorescence microscopy and high-dimensional mass cytometry by time-of-flight (CyTOF) using an antibody panel of immune cell markers. Changes in cardiac physiologic parameters were measured up to 60 days postpartum via two-dimensional echocardiography. Results: Intravaginal E. coli administration resulted in preterm delivery of live pups in 70% of the cases. mT + expressing cells were detected in maternal uterus and heart, implying that fetal cells can migrate to different maternal compartments. During ascending infection, more fetal antigen-presenting cells (APCs) and less fetal hematopoietic stem cells (HSCs) and fetal double-positive (DP) thymocytes were observed in maternal hearts at E16 compared to normal pregnancy. These HSCs were cleared while DP thymocytes persisted 28 days postpartum following an ascending infection. No significant changes in cardiac physiologic parameters were observed postpartum except a trend in lowering the ejection fraction rate in preterm delivered mothers. Conclusion: Both normal pregnancy and ascending infection revealed distinct compositions of fetal microchimeric immune cells within the maternal heart, which could potentially influence the maternal cardiac microenvironment via (1) modulation of cardiac reverse modeling processes by fetal stem cells, and (2) differential responses to recognition of fetal APCs by maternal T cells.

Poor glucose control and markers of placental dysfunction correlate with increased circulating fetal microchimerism in diabetic pregnancies.

Fetal microchimerism (FMc) arises during pregnancy as fetal cells enter maternal circulation and remain decades postpartum. Circulating FMc is increased in preeclampsia, fetal growth restriction, and as we recently showed, is associated with biomarkers of placental dysfunction in normotensive term pregnancies. Diabetes mellitus (DM) also correlates with placental dysfunction. We hypothesize that poor glucose control and markers of placental dysfunction are associated with increased circulating FMc in diabetic pregnancies. We included 122 pregnancies preceding active labor (pregestational DM, n = 77, gestational DM (GDM), n = 45) between 2001 and 2017. Maternal and fetal samples were genotyped for various human leukocyte antigen (HLA) loci, and other polymorphisms to identify fetus-specific alleles. We used validated polymerase chain reaction (PCR) assays to quantify FMc in maternal peripheral blood buffy coat. Negative binomial regression with adjustment for confounders was used to assess FMc quantity. In pregestational DM, increased circulating FMc correlated with elevation of HbA1c (≥ 6.0 %) (detection rate ratio (DRR) = 4.9, p = 0.010) and a 1000 pg/mL rise in the anti-angiogenic biomarker soluble fms-like tyrosine kinase-1 (sFlt-1) (DRR = 1.1, p = 0.011). In GDM, increased FMc correlated with elevated 2-hour oral glucose tolerance test results (DRR = 2.3, p = 0.046) and birthweight < 10th or > 90th percentile (DRR = 4.2, p = 0.049). These findings support our novel hypothesis that FMc correlates with poor glucose control and various aspects of placental dysfunction in DM. Whether increased FMc in pregnancies with poor glucose control and placental dysfunction contributes to the risk of preeclampsia in diabetic pregnancies and to the increased risk of chronic cardiovascular disease later in life remains to be investigated.

Influence of Fetomaternal Microchimerism on Maternal NK Cell Reactivity against the Child's Leukemic Blasts.

Persistence of fetal cells in the circulation of the mother (fetal microchimerism, FM) is associated with increased survival and reduced relapse of children with leukemia receiving a haploidentical hematopoietic stem cell transplantation (hHSCT). NK cells play an important role in maternal tolerance towards the unborn child. In this study, 70 mother-child pairs were prospectively analyzed for the occurrence of FM, KIR genotype and HLA-C type. We found that occurrence and level of FM were influenced by three maternal genetic factors: presence of an HLA-C1 allele, absence of KIR2DL3 and presence of a cen-B/B motif. Furthermore, an HLA-C match between mother and child favored persistence of FM. NK cells from FM+ mothers showed a 40% higher specific degranulation against their filial leukemic blasts than NK cells from FM- mothers, suggesting the presence of educated maternal NK cells. Nevertheless, cytotoxicity of parental NK cells against filial leukemic blasts was independent of KIR genetics (haplotype, B content score, centromeric and telomeric KIR gene regions) and independent of FM, indicating that additional immune effector mechanisms contribute to the beneficial effect of persisting FM in hHSCT.

Fetal microchimerism and implications for maternal health.

This review paper outlines the definition, pathophysiology, and potential maternal health consequences of cellular fetal microchimerism, the maternal acquisition of intact cells of fetal origin during pregnancy. Increased rates and amounts of cellular fetal microchimerism are associated with several placental syndromes, including preeclampsia and fetal growth restriction. The discovery of cellular fetal microchimerism and methods of detection are briefly outlined, and we present the mechanisms hypothesized to govern pregnancy-related and long-term maternal health effects of cellular fetal microchimerism. Specifically, we discuss the potential implications of cellular fetal microchimerism in wound healing, autoimmunity, cancer, and possibly cardiovascular disease. Cellular fetal microchimerism represents a novel area of research on maternal and transgenerational health and disease, providing exciting opportunities for developing new disease biomarkers and precision medicine with targeted prophylaxis against long-term maternal disease.

Fetal microchimerism in human brain tumors.

Sex differences in cancer incidence and survival, including central nervous system tumors, are well documented. Multiple mechanisms contribute to sex differences in health and disease. Recently, the presence of fetal-in-maternal microchimeric cells has been shown to have prognostic significance in breast and colorectal cancers. The frequency and potential role of these cells has not been investigated in brain tumors. We therefore selected two common primary adult brain tumors for this purpose: meningioma, which is sex hormone responsive and has a higher incidence in women, and glioblastoma, which is sex hormone independent and occurs more commonly in men. Quantitative PCR was used to detect the presence of male DNA in tumor samples from women with a positive history of male pregnancy and a diagnosis of either glioblastoma or meningioma. Fluorescence in situ hybridization for the X and Y chromosomes was used to verify the existence of intact male cells within tumor tissue. Fetal microchimerism was found in approximately 80% of glioblastoma cases and 50% of meningioma cases. No correlations were identified between the presence of microchimerism and commonly used clinical or molecular diagnostic features of disease. The impact of fetal microchimeric cells should be evaluated prospectively.

Donor mesenchymal stem cells home to maternal wounds after transamniotic stem cell therapy (TRASCET) in a rodent model.

PURPOSE: Transamniotic stem cell therapy (TRASCET) with amniotic fluid-derived MSCs (afMSCs) has emerged experimentally as a practical treatment strategy for congenital anomalies. In this study, we sought to determine whether afMSCs migrate to the mother following TRASCET. METHODS: Pregnant rat dams were divided into three groups. Two groups received volume-matched injections into all amniotic cavities of either a suspension of afMSCs labeled with a luciferase reporter gene or the luciferase protein alone. In a third group, a suspension of labeled cells was aliquoted onto the serosal surface of the uterus. Maternal samples from the laparotomy scar (fascia and skin separately), bone marrow, and peripheral blood were procured, along with placenta and umbilical cord. Specimens were screened for luminescence via microplate luminometry. RESULTS: Luminescence was detected in 60% (9/15) of the fascial scars from the group receiving intraamniotic injection of afMSCs, but in none of the other groups (P<0.001). There was a direct correlation between the presence of donor cells in the placenta and their presence in maternal fascia (Wald test=10.2; P=0.001). CONCLUSIONS: Amniotic mesenchymal stem cells migrate to maternal sites of injury after intraamniotic injection. Maternal homing of donor cells must be considered in the setting of transamniotic stem cell therapy. LEVEL OF EVIDENCE: N/A (animal and laboratory study).

Variables associated to fetal microchimerism in systemic lupus erythematosus patients.

In the present study, we sought to identify the factors during the pregnancy of systemic lupus erythematosus (SLE) patients that could be linked to the presence and proliferation of male fetal cells (MFC) and the possible relation between these factors and development of lupus nephritis (LN). We evaluated 18 healthy women (control group) and 28 women affected by SLE. Genomic DNA was extracted from peripheral blood and quantified using the technique of quantitative real-time polymerase chain reaction (qPCR) for specific Y chromosome sequences. The amount of MFC was significantly higher in the SLE group compared with the controls (SLE 252 ± 654 vs control 2.13 ± 3.7; P = 0.029). A higher amount of MFC was detected among multiparous SLE patients when compared with the control group (SLE 382 ± 924 vs control 0.073 ± 0.045; P = 0.019). LN was associated with reduced amount of MFC (LN 95.5 ± 338 vs control 388 ± 827; P = 0.019) especially when they have delivered their child before age 18 (LN 0.23 ± 0.22 vs control 355 ± 623; P = 0.028). SLE patients present a higher amount of MFC, which may increase with the time since birth of the first male child. LN patients showed an inverse correlation with MFC, suggesting that the role of the cells may be ambiguous during the various stages of development of the disease.

Lack of Evidence That Male Fetal Microchimerism is Present in Endometriosis.

INTRODUCTION: Fetal microchimerism has been implicated in the etiology of autoimmune diseases. This study was done to test the hypothesis that male fetal microchimerism is present in eutopic and ectopic endometrium (EM) obtained from women with endometriosis but not in eutopic EM from women without endometriosis. METHODS: A total of 31 patients were selected, including women with endometriosis (paired eutopic and ectopic EM; n = 19) and women without endometriosis (eutopic EM; n = 12). Tricolor interphase fluorescence in situ hybridization analysis was performed by cohybridization of CEP Y SpectrumAqua and CEP X SpectrumGreen (SG)/CEP Y SpectrumOrange probes. RESULTS: Ectopic EM from women with endometriosis had 75% XX chromosomes (double SG signals) and 25% X chromosomes (single SG signal). Y chromosomes were not observed in any of the eutopic/ectopic endometrial tissues from cases or controls. CONCLUSIONS: We were unable to confirm our hypothesis that male fetal microchimerism is present in eutopic and/or ectopic EM obtained from women with endometriosis.

Positive effect of fetal cell microchimerism on tumor presentation and outcome in papillary thyroid cancer.

Studies on both circulating and tissue fetal cell microchimerism (FCM) favored its protective role in thyroid cancer, consistent with findings in other malignancies. Nevertheless, scanty data were available on the possible impact on the outcome of the disease. We demonstrated that FCM has a positive effect on thyroid cancer presentation and outcome. We also excluded that the better clinical features observed were due to the effect of pregnancy per se. In conclusion, FCM may have not only a protective role toward the onset of thyroid cancer, but also a positive effect on its progression. These findings give novel insights into the identification of the role of FCM in oncology and, consequently, in the potential therapeutic application of this physiological phenomenon.

Microchimeric fetal cells play a role in maternal wound healing after pregnancy.

Fetal cells persist in mothers for decades after delivery: in a phenomenon called fetal microchimerism. While persistent fetal cells were first implicated in autoimmune disease, parallel studies in animal and human pregnancy now suggest that microchimeric fetal cells play a role in the response to tissue injury. The aim of this study was to investigate the impact of fetal microchimeric cells in the adult wound, using caesarean section (CS) as a model of wound healing in pregnancy. XY-FISH (fluorescence in situ hybridization) and immunostaining was used in multiple tissue sections from CS skin biopsies from 70 women, to locate, quantitate and characterize microchimeric male presumed-fetal cells. Y-FISH and Nested PCR was used to confirm XY-FISH results. XY-FISH demonstrated the presence of isolated 0-9 male fetal cells per section in the epidermis of the healed CS scars from only those women who had their first male child by CS. Both Y-FISH and Y-PCR confirmed the presence of fetal cells in CS scars. Combined FISH and immunostaining showed all male fetal cells present were keratinocytes, as they expressed cytokeratin, and were almost exclusively located in epidermis. Microchimeric fetal cells also expressed Collagen I, III, and TGF-ß3 in healed maternal scars. Identification of male-presumed fetal cells in healed maternal CS scars after pregnancy suggests that, possibly in response to signals produced by maternal skin injury at CS, fetal cells migrate to the site of damage to become involved in maternal tissue repair, or proliferate locally.

The health effects of fetal microchimerism can be modeled in companion dogs.

Fetal microchimerism (FMC) has been described to have a range of effects on health and disease. Y-chromosomal DNA has been detected in Golden Retrievers suggesting persistent FMC. In that report, nine dogs had evidence of microchimerism without prior pregnancy. To further understand this finding, a dam with prior male live births giving birth to her fourth litter of puppies, all females, was evaluated for FMC along with two of her daughters. All three female dogs had evidence of Y-chromosomal DNA in their blood. This suggests that male cells carried by the dam from previous pregnancy trafficked to her daughters to establish microchimerism in younger siblings. Companion dogs share many of the same cancers as humans, have out-bred genetics, and share the human environment, making them optimal models of human disease. Understanding the impact of FMC on health and disease of dogs could elucidate mechanisms useful for clinical interventions in humans.