Marker tolerant, immunocompetent animals as a new tool for regenerative medicine and long-term cell tracking

Transplantation of cells from hPLAP transgenic (hPLAP-tg) F344 rats into wild-type (WT) F344 recipients failed because of immune-mediated rejection. Here we show that this problem can be overcome by inducing tolerance to the marker gene by transplantation of bone marrow from hPLAP-tg F344 rats into WT F344 hosts after lethal irradiation, or by neonatal exposure of WT F344 rats to hPLAP-tg F344 cells. As proof-of-principle, we injected bone marrow cells (BMC) from hPLAP-tg rats into the knee joint of marker tolerant, bone marrow-transplanted WT rats, and found successful engraftment and differentiation of donor cells. In addition, hPLAP-tg BMC injected intravenously in neonatally tolerized WT F344 hosts could be traced in lymph nodes, 2 months post-injection.In combination with the excellent marker hPLAP, marker tolerant animals may open up new perspectives for all experiments requiring long-term histological tracking of genetically labeled cells.Cell therapy or cell-based gene therapy with adult pluripotent mesenchymal stem cells is thought to revolutionize the treatment of a large variety of diseases of various organ systems in the future [reviewed in [1]]. To further explore the therapeutic potential of regenerative treatment protocols, appropriate animal models are necessary that allow tracing the fate of individual donor or manipulated cells in the host organism.Tracing of cells requires labeling, and one standard approach to label cells is to introduce marker genes into the genome of the cells under investigation. Marker genes can either be permanently integrated into the genome of transgenic animals so that all or at least some somatic cells are permanently labeled, or wild-type cells can be transduced with vectors containing the marker gene. A stable genetic marker is especially useful for cell lineage experiments, because the marker is expressed in whole progeny of a specific cell.Recent work from our laboratory has shown that human placental alkaline phosph