Microchimerism – The More, The Merrier

by Una Choi

Microchimerism, or the presence of genetically distinct populations within a single organism, throws a wrench in the biological concept of sex. Although we traditionally learn that biological females possess two X sex chromosomes and males possess X and Y sex chromosomes, microchimerism is responsible for the presence of cells with Y chromosomes in females. Microchimerism can result from a variety of factors ranging from organ transplant to in-utero transfer between twins. Recent research has focused primarily on maternal microchimerism (MMc) in relation to cord blood transplantation and fetal microchimerism (FMc), the two most common forms of microchimerism.

BI-DIRECTIONAL EXCHANGE DURING PREGNANCY

The placenta connects the mother and fetus, facilitating the bi-directional exchange of cells. Low-level fetal Y-chromosome DNA is found in maternal cellular and cell-free compartments starting at the seventh week of pregnancy and peaks at childbirth.¹ Although fetal DNA rapidly disappears from the mother’s body after labor, fetal cells can persist in the mother’s body for decades and vice versa.² Indeed, there are around two to six male fetal nucleated cells per milliliter of maternal blood,³ and 63% of autopsied female brains exhibited male microchimerism.⁴

The cells crossing the placenta possess varied physical features and durations in the host body. Highly differentiated cells like nucleated placental trophoblasts, which provide nutrients to the placenta, do not remain for long in maternal circulation. In contrast, pre-natal-associated progenitor cells (PAPCs) can persist for decades after birth. These microchimeric progenitor cells, like stem cells, can differentiate into specific types of cells. PAPCs can later become hematopoietic, or blood-forming, cells and epithelial cells.⁵ PAPCs have also been found in murine brains. A 2010 study found that PAPCs remained in the maternal brain for up to seven months. These PAPCs developed mature neuronal markers, suggesting their active integration into the maternal brain.⁶

BENEFITS OF MMC IN CORD BLOOD TRANSPLANTATION

Maternal microchimerism, or the presence of maternal cells in the fetus, is responsible for the consistent success of cord blood transplants. Cord blood is extracted from the umbilical cord and placenta. Because cord blood is rich in hematopoietic stem cells, it is often used as treatment for leukemia. Transplants, however, are not without risk; the introduction of foreign material may cause graft-versus-host-disease (GVHD). GVHD occurs when the donor’s immune cells target the patient’s healthy tissue.

Cord blood inherently contains both maternal cells and fetal cells due to the previously mentioned bi-directional exchange. This displayed MMc can diminish the risks accompanying cord blood transplants.⁷ The fetus benefits from human leukocyte antigens (HLAs) present on the maternal cells. These HLAs encode for regulating proteins involved in the human immune system. The HLA system can present antigens to T-lymphocytes, which trigger B-cells to produce antibodies.⁸

Unlike bone marrow and peripheral blood transplants, HLA matching between cord blood donor and recipient does not have to be exact. Indeed, it is often imprecise due to the large variety of HLA polymorphisms;⁹ parents are often HLA heterozygous because HLA loci are extremely variable. While the foreign maternal cells could potentially aggravate GVHD, cord blood recipients actually exhibit low rates of relapse. Indeed, maternal anti-inherited paternal antigens (IPA) immune elements may result in a graft-versus-leukemia effect.¹⁰ The graft-versus-leukemia effect describes the role of donated cytotoxic T lymphocytes in attacking malignant tumors.

Exposing a fetus to foreign antigens can result in lifelong tolerance; fetal tolerance is strongest against maternal antigens.⁷ In HLA-mismatched cord blood transplants, patients displayed more rapid engraftment, which features the growth of new blood-forming cells and is a marker of transplant recovery, diminished GVHD, and decreased odds of a leukemia relapse. Indeed, the relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without the disease.¹¹

IMMUNE SURVEILLANCE AND FMc

The benefits of microchimerism are not limited to the recipients of maternal cells. The mothers themselves often benefit from increased immune surveillance. Indeed, fetal microchimeric cells T cells can eradicate malignant host T-cells.

Microchimeric cells can also provide protection against various forms of cancer. During pregnancy, mothers can develop T- and B-cell immunity against the fetus’s IPAs. This anti-IPA immunity persists for decades after birth, reducing risk of leukemia relapse. PAPCs can differentiate into hematopoietic cells, which are predicted to have a role in destroying malignant tumors.¹² In a study of tissue section specimens from women who had borne sons, 90% of hematopoietic tissues like lymph nodes and spleen expressed CD45, a leukocyte antigen previously identified in the male cells.¹³

PAPCs are also associated with decreased risk for breast cancer; circulating fetal cells are only found in 11-26% of mothers with breast cancer while a study of 272 healthy women found male microchimerism in 70% of the participants, suggesting microchimerism’s role in the maintenance of a healthy stasis.^14,15 The depletion of PAPCs in breast cancer patients may result from the migration of PAPCs from the bloodstream to the tumor.¹⁶

AUTOIMMUNE CONDITIONS

FMc and MMc are common in healthy individuals and are associated with repression of autoimmune conditions. Rheumatoid arthritis (RA) is a genetic disorder stemming largely from coding in the HLA-region. The molecules coded for in the HLA-region contain the amino acid sequence DERAA, which is associated with defense against RA. Of 179 families studied, the odds of producing at least one DERAA-negative child from a DERAA-positive mother are significantly lower than the odds of producing a DERAA-negative child with a DERAA-positive father. This suggests a protective benefit of non-inherited maternal HLA-DR antigens in decreasing susceptibility to RA.¹⁷

ORGAN REGENERATION

Fetal stem cells feature longer telomeres and superior osteogenic potential than their adult counterparts. They also express embryonic pluripotency markers like Oct4.¹⁶ These fetal cells are connected to the alleviation of myocardial disease. In a 2011 study, pregnant mice with myocardial injuries exhibited a transfer of fetal cells from the bloodstream to the site of injury, where the fetal cells differentiated into various types of cardiac cells.¹⁸ 40% of PAPCs extracted from the heart expressed Cdx2, a caudal homeobox gene expressed during development. Cdx2 differentiates cells that will become the trophectoderm, or the outer layer of the blastoderm which provides nutrients to the placenta, from cells that will become the inner cell mass. Because Cdx2 is absent in the mature trophoblast, the extracted cells likely originated in the placenta.¹⁹

A recent study used fluorescence activated cell sorting (FACS) to analyze fetal green fluorescent protein (eGFP+) cells’ in vitro behavior. These fetal cells exhibited clonality and differentiated into smooth muscle cells and endothelial cells, displaying beneficial implications for organ regeneration.

PAPCs selectively travel to damaged organs, further emphasizing their role in healing. eGFP+ cells were present in low quantities in all tissues until the 4.5th day after the injury. 1.1% of the cells were eGFP+ before injury while 6.3% were eGFP+ after delivery, thus displaying a significant increase. These findings pose significant implications for maternal health; PAPCs may be at least partly responsible for the spontaneous recovery from heart rate exhibited by 50% of women.¹⁸

FUTURE IMPLICATIONS

Microchimerism poses important implications for cord blood transplants. If we know the maternal and fetal HLA, we can match recipients with those donors whose IPA are included in the recipient’s HLA type to promote graft acceptance.

Although cord blood is typically preserved for transplants, the placenta is often discarded after childbirth. If PAPCs can be traced back to the placenta, the placenta may provide a valuable source of undifferentiated stem cells capable of organ regeneration. Although placental tissue and amniotic fluid have less differentiation potential than fetal tissue from pregnancy terminations, they are less controversial sources of stem cells.¹⁶

Because FMc plays an active role in the mother’s body for decades, it can impart significant benefits. The selective migration of PAPCs to damaged organs suggests the existence of a specific targeting mechanism. The ability of extracted PAPCs to differentiate in vitro into working cardiovascular structures also poses exciting implications for organ synthesis.

Una Choi ‘19 is a freshman in Greenough Hall.

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