Transplacental bidirectional trafficking of cells from the fetus to the mother occurs in all human pregnancies [1
]. Although the exact purpose of this cellular exchange is unknown, it is thought to be important in development of immune tolerance of the mother to the fetus and vice versa [3
]. Substantial numbers of maternal cells cross the placenta and travel to the fetal lymph nodes where they induce production of fetal T-regulatory cells (T-regs). The anti-maternal fetal T-regs persist into adulthood [3
Similarly, microchimeric fetal cells persist in the maternal circulation and/or tissue without evidence of graft rejection. This has given rise to the term fetal cell microchimerism
]. Fetal cells can be identified for decades after the pregnancy [2
]. Therefore, as a result of pregnancy, females acquire populations of cells that have unknown effects on their health. One hypothesis is that fetal cells might trigger a graft-versus-host reaction leading to autoimmune disease. This offers a potential explanation for why many autoimmune diseases are more prevalent in middle-aged women [9
]. The other main theory is that fetal cells home to injured or diseased maternal tissue where they act as stem cells and participate in repair [10
]. It is also possible that the fetal cells are merely innocent bystanders and have no effect on maternal health [12
Despite the fact that the specific health implications of fetal cell microchimerism have yet to be definitively determined, a growing body of literature points towards disproportionately increased fetal cell presence at sites of injury. Khosrotehrani et al. [13
] showed in a pregnant murine model that the number of fetal cells in the maternal liver increased in response to a chemical injury induced by carbon tetrachloride. Other researchers showed that skin and spinal cord injuries in pregnant mice resulted in significantly more fetal cells at the site of injury [14
Taken together, the current literature suggests that a sub-population of microchimeric fetal cells possess properties similar to stem cells. They have been called “pregnancy-associated progenitor cells,” or PAPCs [10
]. Evidence exists to suggest that at least some of the fetal cells are hematopoietic stem cells, while other research suggests that some are mesenchymal stem cells [15
]. If such studies are validated, fetal cells could potentially be harvested, expanded in vitro
, and reintroduced to the mother to aid in tissue repair. Together with the exogenous stem cell therapies currently being studied, PAPCs should be explored as a novel source of stem cells. Because PAPCs preferentially traffic to the maternal lung [16
] they may play an especially important role in lung disease.
Many acute and chronic lung diseases are currently incurable. Despite significant advances in symptomatic care, the only option for many patients is transplantation. This is not a guaranteed cure, as lung transplantation has a 50% mortality rate at 5 years [17
]. Innovative therapies could have a significant impact on the morbidity and mortality of lung diseases. Exogenously administered stem cells are currently being investigated as novel therapeutic approaches for many lung diseases, including chronic obstructive pulmonary disease (COPD), emphysema, pulmonary fibrosis, pulmonary hypertension and acute respiratory distress syndrome [18
]. Although there is currently little experience using stem cells for treatment of lung diseases, preliminary results from animal models and clinical trials are promising.
Physicians and researchers alike have long recognized the presence of sex differences in lung diseases. Idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension and lymphangiomyomatosis (LAM) are all more prevalent in females [18
]. Emphysema in males is typically more extensive and characterized by greater peripheral involvement and larger emphysematous areas compared to females [19
]. Additionally, there are sex differences in the prognosis of acute respiratory distress syndrome, with men having a much higher mortality rate [20
]. Most studies addressing this issue have focused on the effects of sex hormones on lung development and progression of disease. Although differences in sex hormones may be responsible for some of these discrepancies, the field has overlooked the potential role of pregnancy and fetal cell microchimerism. This is especially important, given the high concentration of PAPCs found in the maternal lung [16
]. In this review we present the current state of stem cell therapies and discuss PAPCs, an under-appreciated and potentially powerful alternative type of stem cell.