Fetomaternal microchimerism: Some answers and many new questions.

The transfer of fetal cells into mothers during pregnancy and their organ specific integration is a well recognized phenomenon in placental vertebrates. Recently, it has been reported that some fetal cells found in the mothers have progenitor cell-like features such as multilineage differentiation potential and as a consequence they were termed pregnancy associated progenitor cells (PAPC). The multilineage differentiation potential suggested some level of cellular plasticity, which these cells share with other stem or progenitor cells. In this context, we have shown that PAPCs indeed express neural stem cell and markers for developing neurons in the brain and that PAPCs morphologically mature into neurons over time. The stem/progenitor properties of PAPCs raises the hope that they might be valuable for studying the functional integration of foreign cells into preexisting tissues and organs, for example in cellular therapies. The functional integration of transplanted cells and their connectivity to the host circuitry is still a major bottleneck in cellular therapies particularly for the brain. The animal models of fetomaternal microchimerism might provide valuable insights into the mechanism how cells survive, migrate, integrate and differentiate in a foreign environment of a host. This review discusses some of the recent findings in the field of fetomaternal microchimerism. It also tries to identify some major gaps of knowledge and raises some questions resulting from the recent advances. Studying fetomaternal microchimerism and the properties of PAPCs in greater detail might pave the way to advance cell based regenerative medicine as well as transplantation medicine.

Pregnancy-associated progenitor cells differentiate and mature into neurons in the maternal brain.

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.

A mouse model for tracking nigrostriatal dopamine neuron axon growth.

The midbrain dopaminergic system, which consists of neurons of the substantia nigra and the ventral tegmental area, is a subject of intense interest, since the loss of neurons from the substantia nigra results in motor disorders characteristic of Parkinson's disease. We have generated a knock-in reporter mouse line with the tau-lacZ fusion gene inserted into the Pitx3 locus via homologous recombination. This approach permitted the visualisation of midbrain specific dopaminergic axonal tracts from both the substantia nigra and the ventral tegmental area in phenotypically normal heterozygous Pitx3-taulacZ brain tissues, either in situ or following culture in vitro, by a simple and sensitive beta-galactosidase enzyme reaction. Thus the Pitx3-taulacZ mice could serve as a valuable tool for the identification of molecules regulating midbrain dopaminergic neuritogenesis, either in vivo in combination with genetic manipulation in mice, or in vitro using organ cultures.

Vps20p and Vta1p interact with Vps4p and function in multivesicular body sorting and endosomal transport in Saccharomyces cerevisiae.

Vps4p (End13p) is an AAA-family ATPase that functions in membrane transport through endosomes, sorting of soluble vacuolar proteins to the vacuole, and multivesicular body (MVB) sorting of membrane proteins to the vacuole lumen. In a yeast two-hybrid screen with Vps4p as bait we isolated VPS20 (YMR077c) and the novel open reading frame YLR181c, for which the name VTA1 has recently been assigned (Saccharomyces Genome Database). Vps4p directly binds Vps20p and Vta1p in vitro and binding is not dependent on ATP - conversely, Vps4p binding to Vps20p is partially sensitive to ATP hydrolysis. Both ATP binding [Vps4p-(K179A)] and ATP hydrolysis [Vps4p-(E233Q)] mutant proteins exhibit enhanced binding to Vps20p and Vta1p in vitro. The Vps4p-Vps20p interaction involves the coiled-coil domain of each protein, whereas the Vps4p-Vta1p interaction involves the (non-coiled-coil) C-terminus of each protein. Deletion of either VPS20 (vps20Delta) or VTA1 (vta1Delta) leads to similar class E Vps- phenotypes resembling those of vps4Delta, including carboxypeptidase Y (CPY) secretion, a block in ubiquitin-dependent MVB sorting, and a delay in both post-internalisation endocytic transport and biosynthetic transport to the vacuole. The vacuole resident membrane protein Sna3p (whose MVB sorting is ubiquitin-independent) does not appear to exit the class E compartment or reach the vacuole in cells lacking Vps20p, Vta1p or Vps4p, in contrast to other proteins whose delivery to the vacuole is only delayed. We propose that Vps20p and Vta1p regulate Vps4p function in vivo.