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 experimentally 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.
Mesenchymal stem cells (MSCs) have multilineage differentiation potential which includes cell lineages of the central nervous system; hence MSCs might be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Although mesenchymal stem cells have been shown to differentiate into the neural lineage, there is still little knowledge about the underlying mechanisms of differentiation particularly towards specialized neurons such as dopaminergic neurons. Here, we show that MSCs derived from human umbilical cord blood (MSChUCBs) are capable of expressing tyrosine hydroxylase (TH) and Nurr1, markers typically associated with DA neurons. We also found differential phosphorylation of TH isoforms indicating the presence of post-translational mechanisms possibly activating and modifying TH in MSChUCB. Furthermore, functional dissection of components in the differentiation medium revealed that dibutyryl-cAMP (db-cAMP), 3-isobutyl-1-methylxanthine (IBMX) and retinoic acid (RA) are involved in the regulation of Nurr1 and Neurofilament-L expression as well as in the differential phosphorylation of TH. We also demonstrate a possible inhibitory role of the protein kinase A signaling pathway in the phosphorylation of specific TH isoforms.
The suitability of various commercially available endothelial cell lines in studies of astrocytic/endothelial cell interactions was assessed. The endothelial-like cell line ECV304 was compared with T24/83, Eahy929, and b.End5 and rat cerebral endothelial cells in their ability, when co-cultured with rat (C6) glioma cells, to form a transendothelial electrical resistance (TEER), an indicator of tight junction formation which is an important property of the blood-brain barrier. As reported previously, the basal TEER of ECV304 cell monolayers was significantly enhanced upon co-culture, an effect reproduced by human 1321N1 astrocytes and primary rat astrocytes. T24/83 cells formed a patchy, gapped monolayer, which produced a poor basal TEER with little in the way of an increase upon co-culture. Similarly, all the other cell monolayers analysed demonstrated poor TEERs that were only moderately increased upon co-culture. These data confirm that while no endothelial cell line with ideal features is available, ECV304 cells remain an appropriate choice especially for studies of astrocyte/endothelial cell interactions.
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