Microchimeric Cells Research Articles

Postnatal depletion of maternal cells biases T lymphocytes and natural killer cells' profiles toward early activation in the spleen.

The maternal cells transferred into the fetus during gestation persist long after birth in the progeny. These maternal cells have been hypothesized to promote the maturation of the fetal immune system in utero but there are still significant gaps in our knowledge of their potential roles after birth. To provide insights into these maternal cells' postnatal functional roles, we set up a transgenic mouse model to specifically eliminate maternal cells in the neonates by diphtheria toxin injection and confirmed significant depletion in the spleens. We then performed immunophenotyping of the spleens of two-week-old pups by mass cytometry to pinpoint the immune profile differences driven by the depletion of maternal cells in early postnatal life. We observed a heightened expression of markers related to activation and maturation in some natural killer and T cell populations. We hypothesize these results to indicate a potential postnatal regulation of lymphocytic responses by maternal cells. Together, our findings highlight an immunological influence of maternal microchimeric cells postnatally, possibly protecting against adverse hypersensitivity reactions of the neonate at a crucial time of new encounters with self and environmental antigens.

CCL2 recruits fetal microchimeric cells and dampens maternal brain damage in post-partum mice

Preventing brain cell loss and enhancing tissue repair are crucial objectives to improve the outcome of stroke. Fetal microchimerism has been implicated in brain repair following ischemic stroke in mice. CCL2/CCR2 signaling pathway triggers fetal progenitors trafficking to cutaneous wounds. Therefore, we sought to evaluate whether CCL2 could dampen brain damage in a model of excitotoxic lesion in post-partum mice.Virgin or post-partum mice were subjected to an intracerebral injection of ibotenate to induce excitotoxic lesions. Low doses of CCL2 or its vehicle were concomitantly injected. Morphological and molecular analyses were performed 1 and 5 days following the procedure.Intracerebral treatment with low doses of CCL2 was able to limit brain excitotoxic damage induced by ibotenate in post-partum mice, through an enhanced recruitment of fetal microchimeric cells to the damaged hemisphere. At day 1 post-injection, we observed a decreased cortical apoptosis associated with a reduced reactive astrocytosis. At day 5, we found an increased proportion of mature neurons and oligodendrocytes correlating with an increase in GAP43 growth cones. At this stage, immune microglial cells were reduced, while angiogenesis was enhanced. Importantly, CCL2 did not have beneficial effects in virgin mice therefore ruling out a specific role of CCL2 independently from fetal microchimeric cells mobilization.CCL2 treatment efficiently enhances fetal cell mobilization to improve the outcome of a brain excitotoxic challenge in post-partum mice. This study paves the way for a “natural stem cell therapy” based on the selective recruitment of fetal progenitors to repair maternal brain injury.

A history of cesarean section and future maternal long-term risk for neoplasms: a population-based cohort study.

Mode of delivery has long-term implications on the mother, including recent data regarding the level of transmission of fetal microchimeric cells (FMc) and their possible effect on cancer development. We aimed to evaluate the association between cesarean section (CS) and future risk for neoplasms. A population-based cohort analysis comparing the long-term risk for neoplasms between patients that delivered only by CS to those that delivered only vaginally (VD). Neoplasms were pre-defined based on ICD-9 codes. Deliveries occurred between the years 1991-2017 in a tertiary medical center. Kaplan-Meier survival curves were used to compare the cumulative incidence of neoplasms and Cox proportional hazards models were constructed to control for confounders. During the study period 105,992 patients met the inclusion criteria; 14150 (13.4%) of patients had only CS and 91842 (86.6%) had VD (comparison group). The CS group had significantly higher incidence of benign and malignant neoplasms (4.73 per 1000 patient-years versus 3.88 per 1000 patient-years, OR = 1.26, 95% CI 1.16-1.37; p = 0.001; 2.19 per 1000 patient-years of follow up versus 1.93 per 1000 patient-years, OR = 1.16, 95% CI 1.03-1.31; p = 0.013). Specifically, the CS group had higher incidence of uterine cancer (1.2 versus 0.06 per 1000 patient-years, OR = 1.97, 95% CI 1.14-3.39; p = 0.013). The cumulative incidence of benign, malignant and uterine neoplasms was significantly higher in the CS group (Log rank test p = 0.001; 0.036 and 0.014; respectively). Importantly, no significant association was found with breast and ovarian malignancies." When performing a Cox regression model controlling for confounders, the risk for malignancy-related hospitalizations remained significant (adjusted HR = 1.22, 95% CI 1.01-1.48; p = 0.031) but not for uterine cancer (adjusted HR = 1.6, 95% CI 0.9-2.8; p = 0.103). Our findings provide support to linkage between delivery by cesarean section and future maternal malignancy.

Pregnancy-induced maternal microchimerism shapes neurodevelopment and behavior in mice

Life-long brain function and mental health are critically determined by developmental processes occurring before birth. During mammalian pregnancy, maternal cells are transferred to the fetus. They are referred to as maternal microchimeric cells (MMc). Among other organs, MMc seed into the fetal brain, where their function is unknown. Here, we show that, in the offspring’s developing brain in mice, MMc express a unique signature of sensome markers, control microglia homeostasis and prevent excessive presynaptic elimination. Further, MMc facilitate the oscillatory entrainment of developing prefrontal-hippocampal circuits and support the maturation of behavioral abilities. Our findings highlight that MMc are not a mere placental leak out, but rather a functional mechanism that shapes optimal conditions for healthy brain function later in life.

Synergies of Extracellular Vesicles and Microchimerism in Promoting Immunotolerance During Pregnancy.

The concept of biological identity has been traditionally a central issue in immunology. The assumption that entities foreign to a specific organism should be rejected by its immune system, while self-entities do not trigger an immune response is challenged by the expanded immunotolerance observed in pregnancy. To explain this “immunological paradox”, as it was first called by Sir Peter Medawar, several mechanisms have been described in the last decades. Among them, the intentional transfer and retention of small amounts of cells between a mother and her child have gained back attention. These microchimeric cells contribute to expanding allotolerance in both organisms and enhancing genetic fitness, but they could also provoke aberrant alloimmune activation. Understanding the mechanisms used by microchimeric cells to exert their function in pregnancy has proven to be challenging as per definition they are extremely rare. Profiting from studies in the field of transplantation and cancer research, a synergistic effect of microchimerism and cellular communication based on the secretion of extracellular vesicles (EVs) has begun to be unveiled. EVs are already known to play a pivotal role in feto-maternal tolerance by transferring cargo from fetal to maternal immune cells to reshape their function. A further aspect of EVs is their function in antigen presentation either directly or on the surface of recipient cells. Here, we review the current understanding of microchimerism in the feto-maternal tolerance during human pregnancy and the potential role of EVs in mediating the allorecognition and tropism of microchimeric cells.

Fetomaternal microchimerism in tissue repair and tumor development.

In various placental mammals, the bidirectional exchange of cells during pregnancy can lead to the acquisition of genetically unique cells that can persist in both mother and child for decades. Over the years, it has become increasingly clear that this phenomenon, termed fetomaternal microchimerism may play key roles in a number of biological processes. In this perspective, we explore the concept of fetomaternal microchimerism and outline how fetal microchimeric cells are detected and immunologically tolerated within the maternal setting. Moreover, we discuss undertakings in the field that hint at the significant plasticity of fetal microchimeric cells and their potential roles in promoting maternal wound healing. Finally, we explore the multifaceted roles of fetal microchimeric cells in cancer development and progression. A deeper understanding of fetomaternal chimerism in healthy and diseased states will be key toward developing more efficient anti-cancer treatments and regenerative therapies.

Cross-decoration of dendritic cells by non-inherited maternal antigen-containing extracellular vesicles: Potential mechanism for PD-L1-based tolerance in cord blood and organ transplantation

Exposure to non-inherited maternal antigens (NIMA) during the fetal period induces lifelong split tolerance to grafts expressing these allo-antigens. In adult mice, the production of extracellular vesicles (EVs) from maternal microchimeric cells causes cross-decoration (XD) of offspring dendritic cells (DC) with NIMA and upregulation of PD-L1, contributing to NIMA tolerance. To see how this may apply to humans, we tested NIMA acquisition by fetal DCS in human cord blood. The average percentage of NIMA-XD among total DCs was 2.6% for myeloid and 4.5% for Plasmacytoid DC. These cells showed higher PD-L1 expression than their non-XD counterparts (mDC: p = .0016; pDC: p = .024). We detected CD9+ EVs bearing NIMA and PD-L1 in cord blood. To determine if this immune regulatory mechanism persists beyond the pregnancy, we analyzed NIMA-expressing kidney and liver transplant recipients. We found donor antigen XD DCs in peripheral blood and graft-infiltrating DCs. As in cord blood, the pattern of donor antigen expression was punctate, and PD-L1 expression was upregulated, likely due to both protein and miRNA acquired from EV. Our findings support a mechanism for split tolerance to NIMAs that develops during pregnancy and is recapitulated in adult transplant recipients.

Effects of Fetal Microchimerism on Female Breast Cancer: State of the Art and Evolutionary Point of View

Introduction: Fetal microchimerism is a frequent phenomenon occurring in all human pregnancies, which allows the transfer of fetal cells of various phenotypes to the mother. Recent data suggest an association between pregnancy, microchimerism, and cancer. A pregnancy history has been identified as a consistent protective factor against breast cancer. Thus, it is conceivable that undefined characteristics of previous pregnancies could explain why some women with positive parity have a reduced risk of breast cancer while others do not. In this context, we undertook this study to evaluate the relationship between fetal microchimerism and female breast cancers through a literature review. Materials and Methods: To meet this objective, namely, to evaluate the relationship between fetal microchimerism and female breast cancer, a literature review was performed using mainly a bibliographic data search engine (Pubmed). Results and Discussion: This study found microchimerism more in healthy women than women with breast cancer, with a statistically significant difference. These results suggest that microchimeric cells may reduce the risk of breast cancer in women. This protective effect may be explained by the differentiation and tissue regeneration properties associated with the immunoregulatory properties of fetal microchimeric stem cells. However, the correlation is not linear. Conclusion: In this study, our results indicate that microchemical cells may help reduce the risk of breast cancer in women. Good knowledge of the mechanisms of these microchemical stem cells could potentially serve as an innovative therapeutic approach for breast cancer patients.

Quantification of Maternal Microchimeric Cells in the Liver of Children With Biliary Atresia.

Biliary atresia (BA) is a rare disorder of unknown etiology. There is a debate as to whether maternal microchimerism plays a significant role in the development of BA or in graft tolerance after liver transplantation. Here, we performed quantitative-PCR-based assays for liver tissues of children with BA and other diseases. Maternal cells were detected in 4/13 and 1/3 of the BA and control groups, respectively. The estimated number of maternal cells ranged between 0 and 34.7 per 106 total cells. The frequency and severity of maternal microchimerism were similar between the BA and control groups, and between patients with and without acute rejection of maternal grafts. These results highlight the high frequency of maternal microchimerism in the liver. This study provides no evidence for roles of microchimerism in the etiology of BA or in graft tolerance. Thus, the biological consequences of maternal microchimerism need to be clarified in future studies.

Addressing microchimerism in pregnancy by ex vivo human placenta perfusion.

The physical connection of mother and offspring during pregnancy allows the bi-directional exchange of a small number of cells through the placenta. These cells, which can persist long-term in the recipient individual are genetically foreign to it and therefore fulfill the principle of microchimerism. Over the last years, pioneer research on microchimeric cells revealed their role in immune adaptation during pregnancy and priming of tolerogenic responses in the progeny. However, the mechanisms involved in cell transfer across the placenta barrier remain poorly investigated. In this review, we summarize the evidence of fetomaternal microchimerism, propose a mechanism for cell trafficking through the placenta and discuss the different models and techniques available for its analysis. Likewise, we aim to generate interest in the use of ex vivo placenta perfusion to investigate microchimerism in physiological and pathological settings.

Whole embryonic detection of maternal microchimeric cells highlights significant differences in their numbers among individuals.

During pregnancy in placental mammals, small numbers of maternal cells (maternal microchimeric cells, or MMc cells) migrate into the fetus and persist decades, or perhaps for the rest of their lives, and higher frequencies of MMc cells are reported to correlate with variety of phenomena, such as immune tolerance, tissue repair, and autoimmune diseases. While detection of these MMc cells is considered in all pregnancies, their frequency differs largely according to tissue type and disease cases, and it remains unclear whether the number of MMc cells differs significantly among embryos in normal pregnancies. Here, for the first time, we developed a whole embryonic detection method for MMc cells using transgenic mice and counted live MMc cells in each individual embryo. Using this technique, we found that the number of MMc cells was comparable in most of the analyzed embryos; however, around 500 times higher number of MMc cells was detected in one embryo at the latest stage. This result suggests that the number of MMc cells could largely differ in rare cases with unknown underlying mechanisms. Our methodology provides a basis for testing differences in the numbers of MMc cells among individual embryos and for analyzing differences in MMc cell type repertoires in future studies. These data could provide a hint toward understanding the mechanisms underlying the variety of apparently inconsistent MMc-related phenomena.

Do Fetal Microchimeric Cells Influence Experimental Autoimmune Myocarditis?

Objective: We investigated the presence and influence of fetal microchimerism in the cardiac tissue of mated female mice submitted to experimental autoimmune myocarditis. Materials and methods: Nulliparous BALB/c females and BALB/c females mated with either BALB/c males (syngeneic mating) or C57BL/6 males (allogeneic mating) were immunized with cardiac myosin peptide MyHC-α614-629 or kept as non-immunized controls. Immunization occurred 6-8 weeks after delivery and mice were assessed after 21 days. Results: Immunized mice of allogeneic mating had a lower production of anti-MyHC-α614–629 antibodies compared to immunized nulliparous mice. Immunized nulliparous females had an intense mononuclear inflammatory infiltrate in cardiac tissue, associated with fibroplasia, while mated females had a lower inflammatory reaction. An increase in the frequency of microchimeric fetal cells was observed in mice submitted to allogeneic mating following immunization. Conclusion: Allogeneic cells of fetal origin could contribute to mitigating the inflammatory response in experimental myocarditis.

Microchimerism in multiple sclerosis: The impact of sex-related differences in fetal-maternal cross-talk on the clinical and radiological phenotype in women with multiple sclerosis

Multiple Sclerosis (MS) is a chronic autoimmune disorder characterised by inflammation and neurodegeneration. Persisting fetal microchimeric cells seem to contribute to autoimmune diseases pathogenesis. The aim of the study is to investigate the impact of microchimerism on the clinical, radiological, and laboratory features of MS.

326 Healing properties of fetal cells beyond pregnancy

Chronic leg ulcers are a severe and disabling condition that still constitute a significant global health issue and for which there has been no therapeutic innovation during the last decades. Sickle cell disease (SCD) leads to prolonged and refractory human ulcers. Fetal microchimeric cells (FMCs) are transferred to mothers during pregnancy and niche into maternal bone marrow where they persist for decades. We have shown that during pregnancy, they are recruited to maternal wounds and improve wound healing. In this work, we sought to evaluate whether the healing capacities of FMCs were sustained after pregnancy in both normal and delayed wound healing in a sickle cell mice model (SAD). We found that healing kinetics were similarly improved in pregnant and post-partum wild-type mice, through increased cell proliferation and angiogenesis. Post-partum SAD mice also showed an accelerated healing compared to virgin mice, associated with the recruitment of FMCs to the wound and increased neovascularization. We then analyzed clinical parameters in both nulliparous or ever-parous women suffering from sickle cell disease and leg ulcers. The analysis of multiple parameters such as number of leg ulcers episodes, hospital admission, infection rate, pain severity and skin graft requirements showed an overall better prognosis in ever-parous SCD women as compared to nulliparous women. Taken together, these results indicate that healing capacities of FMCs are maintained long after delivery. This supports a potential therapeutic use of FMCs to treat delayed wound healing in post-partum women.

Detecting fetal-derived microchimeric cells in maternal tissues involved in maternal behaviour and energetics

Detecting fetal-derived microchimeric cells in maternal tissues involved in maternal behaviour and energetics

Vertically transferred maternal immune cells promote neonatal immunity against early life infections

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens.

Chimerism as the basis for organ repair.

Organ and tissue repair are complex processes involving signaling molecules, growth factors, and cell cycle regulators that act in concert to promote cell division and differentiation at sites of injury. In embryonic development, progenitor fetal cells are actively involved in reparative mechanisms and display a biphasic interaction with the mother; and there is constant trafficking of fetal cells into maternal circulation and vice versa. This phenomenon of fetal microchimerism may have significant impact considering the primitive, multilineage nature of these cells. In published work, we have reported that fetal-derived placental cells expressing the homeodomain protein CDX2 retain all "stem" functional proteins of embryonic stem cells yet are endowed with additional functions in areas of growth, survival, homing, and immune modulation. These cells exhibit multipotency in vitro and in vivo, giving rise to spontaneously beating cardiomyocytes and vascular cells. In mouse models, CDX2 cells from female placentas can be administered intravenously to male mice subjected to myocardial infarction with subsequent homing of the CDX2 cells to infarcted areas and evidence of cellular regeneration with enhanced cardiac function. Elucidating the role of microchimeric fetal-derived placental cells may have broader scientific potential, as one can envision allogeneic cell therapy strategies targeted at tissue regeneration for a variety of organ systems.

Examining immunological tolerance through the lens of reproduction

Abstract Pregnancy is generally considered an “immunological conundrum” whereby a mother must circumvent immunological rules dictating binary “self” vs “non-self” antigen distinction to tolerate her genetically-foreign baby. However, considering reproductive success is the primary biological imperative for all species, it has likely served as an important driver of immune development across mammalian evolution. In other words, reproductive tolerance is not an exception to these rules but serves as a selective pressure continually refining our immune development. To this end, we have begun investigating the long-term impacts of the bi-directional exchange of intact maternal and fetal cells during pregnancy that persist systemically at low, microchimeric levels in mother and child decades after delivery. We believe these genetically-foreign microchimeric cells are not accidental souvenirs of pregnancy, but are instead intentionally preserved to promote tolerogenic memory to both fetal-paternal and non-inherited maternal alloantigens encountered during pregnancy. Thus, we have developed animal pregnancy models and cutting-edge tools that allow selective manipulation of maternal and fetal microchimeric cells together with dynamic tracking of antigen-specific immune responsiveness to these genetically-foreign cells during and after pregnancy. Viewing reproductive success as a strong driver of our immunological evolution, uncovering tolerance mechanisms employed during and after pregnancy will not only inform strategies for amelioration of pregnancy complications but applies in other clinical settings where the ability to regulate immune tolerance is desired (e.g. transplantation, cancer, persistent infection).

Interventional Strategies to Delay Aging Related Diseases & Conditions of the Musculoskeletal System

Aging leads to several geriatric syndromes including frailty, a condition characterized by loss of functional reserve and tissue regeneration repair capacity. Frail individuals exhibit significant mobility and psychological deficits resulting in significant healthcare costs. Thus, identifying strategies to delay aging, or prevent the progressive loss of tissue homeostasis and functional reserve associated with frailty, will dramatically restore function and independence in millions of elderly patients and significantly improve quality of life. We have demonstrated that bone marrow‐derived mesenchymal stem cells (MSCs) and muscle‐derived stem/progenitor cells (MDSPCs) become dysfunctional with age. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, increased metabolic activity, and importantly, resistance to apoptosis. Senescent cells can release pro‐inflammatory cytokines/chemokines, proteases, and other factors known as the senescence‐associated secretory phenotype (SASP). The SASP can adversely affect not only neighboring cells, but also likely contributes to driving systemic aging. Compounds that selectively target and kill senescent cells were recently identified and characterized. These senolytic drugs target and inhibit anti‐apoptotic pathways that are upregulated in senescent cells thereby inducing apoptotic cell death and abrogating systemic SASP factors. Importantly, senolytic drugs have a favorable safety profile being either FDA approved (dasatinib) or over the counter flavonoid supplements (quercetin, fisetin), positive findings may be more readily translatable to Phase I–II clinical trials. Further, it has been reported that exposure to factors present in the serum of young mice restores the regenerative capacity of aged progenitor cells, through parabiotic pairing. We believe that pregnancy represents a unique biological model of a naturally‐shared circulatory system between young and old organisms. Our preliminary data have demonstrated improved musculoskeletal tissue healing after injury in pregnant mice and improved differentiation capacity of aged muscle progenitor cells (MPCs) after stimulation with serum from pregnant mice. We hypothesize that circulating factors from fetal microchimeric cells (FMCs) during pregnancy have beneficial effects on maternal wound healing, such as reduction in fibrosis for optimal tissue regeneration. In summary, we believe these novel interventional strategies could be used to restore the endogenous stem cell populations in age‐related disorderst to promote healthy aging & to delay age‐related disorders.

Human Chorionic Gonadotropin Improves the Proliferation and Regenerative Potential of Bone Marrow Adherent Stem Cells and the Immune Tolerance of Fetal Microchimeric Stem Cells In Vitro.

Nongonadal tissues express luteinizing hormone-chorionic gonadotropin receptors (LHCG-R) which are essential for their growth during fetal development. Adult mesenchymal stem/stromal cells (MSCs) have been shown to express functional LHCG-R outside pregnancy conditions, making them susceptible to hCG stimulation. In the present study we tested the effect of hCG treatment on bone marrow (BM) derived adherent stem cells in vitro, isolated from a parous women, mother of male sons, in order to evaluate its effect on maternal MSCs and in the same time on fetal microchimeric stem cells (FMSCs), to better understand the outcomes of this safe and affordable treatment on cell proliferation and expression of pluripotency genes. Our study highlights the beneficial effects of hCG exposure on gene regulation in bone marrow adherent stem cells through the upregulation of pluripotency genes and selection of more primitive mesenchymal stem cells with a better differentiation potential. Validation of these effects on MSCs and FMSCs long after parturition in vivo represents a close perspective as it could set the premises of a new mobilization strategy for the stem cell transplantation procedures in the clinical setting.