HUMAN FETAL NEOCORTICAL TISSUE GRAFTED TO RAT-BRAIN CAVITIES SURVIVES, LEADS TO RECIPROCAL NERVE-FIBER GROWTH, AND ACCUMULATES HOST IGG

The human-to-rat xenograft approach offers possibilities to study aspe cts of primate cortex development and function without monkeys. Human fetal cortical tissue was grafted to prepared cortical cavities of imm unosuppressed host rats. Fetal tissue fragments were collected after r outine low-pressure vacuum aspiration abortions performed in the first trimester of gestation. Human derived neurons and human nerve fiber o utgrowth were visualized by immunohistochemistry with antibodies again st human neurofilament protein 70 kD (hNFP70). Ingrowth from rat host striatum or cortex into the grafts was analyzed by immunohistochemistr y with antibodies against tyrosine hydroxylase. Astrocytes were evalua ted by immunohistochemistry with antibodies against glial fibrillary a cidic protein. The grafts grew into different sizes (1-10 mm in diamet er) and contained large numbers of hNFP70-positive nerve fibers. All g rafts gave rise to outgrowth of hNFP70-positive fibers into the host w ith partly a cortical layering; layers III and IV received a majority of the human fibers. In several cases, the graft-derived nerve fibers entered the host brain at restricted areas, while there was no crossin g over of nerve fibers at the rest of the graft-host interface. Tyrosi ne hydroxylase-positive fibers were usually not abundant in the grafts . Interestingly, cases of massive ingrowth occurred from host striatum into the graft in a pattern suggesting ''permissive sites'' at the gr aft-host interface in the same way as outgrowth from graft to host was found. Additionally, tyrosine hydroxylase-immunoreactive fibers from host cortex were found to grow into the transplant. Glial fibrillary a cidic protein immunoreactivity was increased at the interfaces between graft and host cortex or host striatum. Immunohistochemistry using an tibodies against rat IgG indicated the presence of rat IgG within the grafts, and in bordering areas of host brain, possibly indicating a de fective graft-host barrier. Taken together, these results show that hu man cortical tissue pieces grafted to cortical cavities of immunosuppr essed rats survive grafting and develop, and that reciprocal nerve fib er growth between grafts and hosts occur. Human cortical neurons can g row into the rat host brain in a pattern which is partly determined by host cortical architecture. (C) 1994 Wiley-Liss, Inc.