ORIGINAL RESEARCH REPORT Pregnancy-Associated Progenitor Cells Differentiate and Mature into Neurons in the Maternal Brain Xiao Xia Zeng, 1 Kian Hwa Tan, 1 Ailing Yeo, 1 Piriya Sasajala, 1 Xiaowei Tan, 2 Zhi Cheng Xiao, 3,4 Gavin Dawe, 2 and Gerald Udolph 1 Bidirectional cell trafficking between fetus and mother during pregnancy is a well-established phenomenon observed in placental vertebrates including humans. Although studies have shown that transmigratory fetal cells, also termed pregnancy-associated progenitor cells (PAPCs), can integrate into multiple maternal organs, the integration, long-term survival, and differentiation of PAPCs in the brain has not been extensively studied. Using a murine model of fetomaternal microchimerism, we show that PAPCs integrated and persisted in several areas of the maternal brain for up to 7 months postpartum. Besides expressing neural stem cell or immature neuronal markers, PAPCs were observed to express mature neuronal markers, indicating that PAPCs adopted a neuronal fate. Further, PAPCs also displayed morphologically neuronal maturation by an increasing axonal= dendritic complexity over time. Therefore, PAPCs seem to undergo a molecular and morphological maturation program similar to that observed during adult neurogenesis. We provide evidence that neuronal gene expression of PAPCs was not a consequence of cell fusion with maternal neurons. In addition, in mothers with experi- mentally induced Parkinson’s disease (PD), the frequency of PAPCs within the hippocampus initially increased whereas long-term presence of PAPCs was compromised. Also, the spatial distribution of PAPCs within the hippocampus was altered in mothers with PD. Thus, the disease context influenced the initial attraction, long- term survival, and spatial distribution of PAPCs, which may have wider implications on cell replacement strategies in human neurodegenerative diseases such as PD. Introduction C ell trafficking between mother and fetus during pregnancy has been described as early as in the 1960s in humans and murine models [1–4]. Maternal cells found in the fetal circulation were identified as leukocytes, granulocytes, and platelets, indicating that the placenta was porous to blood-related cell types. More recently, it has been shown that maternal cells are found in multiple tissues of the fetus, in- cluding the liver, spleen, and thymus [5] as well as the fetal bone marrow [6], suggesting that non-blood-related cells types also cross the placenta. Similar cell migration from fetus to mother has also been demonstrated. Fetal cells have been found in the maternal circulation [7] and they were shown to persist for almost 3 decades in humans, thus demonstrating long-term engraftment and survival capabilities [8]. Although fetal cell engraftment in mothers is generally a rare event, they have the capacity to home into a multitude of organs and tissues such as the peripheral blood, bone marrow, thymus, liver, lung, spleen kidney, skin, and brain. The phenomenon of a small number of genetically distinct fetal cells within organs and tissues of mothers is called fetomaternal micro- chimerism [9–12]. Initially, fetal cells were suggested to cause or contribute to maternal malignancies such as autoimmune diseases [13–19]. However, the presence of fetal cells does not necessarily correlate with any particular disease; and further, fetal cells can express tissue-specific cell markers. This sug- gested that fetal cells integrated and adopted tissue-specific cell fates and possibly contributed to regeneration [20]. It has also been suggested that fetal cells are attracted to cancerous tissues and tissue injuries, where they might also have a re- generative rather than a pathological function [11,12,21–24]. In summary, fetal cells as a population are suspected to have multilineage differentiation capabilities, because they be- haved similarly to stem or progenitor cells [20]. As a conse- quence, they were termed pregnancy-associated progenitor cells (PAPCs) [25]. However, the homing and differentiation potential of PAPCs in multiple brain areas and their long-term 1 Institute of Medical Biology, Singapore, Singapore. 2 Department of Pharmacology, Yong Loo Lin School of Medicine, Clinical Research Center, National University of Singapore, Singapore, Singapore. 3 Institute of Molecular and Clinical Medicine, Kunming Medical College, Kunming, China. 4 R&D China, GlaxoSmithKline, Shanghai, China. STEM CELLS AND DEVELOPMENT Volume 19, Number 12, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089=scd.2010.0046 1