title: Human fetal neocortical tissue grafted to rat brain cavities survives, leads to reciprocal nerve fiber growth, and accumulates host IgG.
abstract: The human-to-rat xenograft approach offers possibilities to study aspects of primate cortex development and function without monkeys. Human fetal cortical tissue was grafted to prepared cortical cavities of immunosuppressed host rats. Fetal tissue fragments were collected after routine low-pressure vacuum aspiration abortions performed in the first trimester of gestation. Human derived neurons and human nerve fiber outgrowth were visualized by immunohistochemistry with antibodies against human neurofilament protein 70 kD (hNFP70). Ingrowth from rat host striatum or cortex into the grafts was analyzed by immunohistochemistry with antibodies against tyrosine hydroxylase. Astrocytes were evaluated by immunohistochemistry with antibodies against glial fibrillary acidic protein. The grafts grew into different sizes (1-10 mm in diameter) and contained large numbers of hNFP70-positive nerve fibers. All grafts gave rise to outgrowth of hNFP70-positive fibers into the host with 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 crossing over of nerve fibers at the rest of the graft-host interface. Tyrosine 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 graft-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 acidic protein immunoreactivity was increased at the interfaces between graft and host cortex or host striatum. Immunohistochemistry using antibodies against rat IgG indicated the presence of rat IgG within the grafts, and in bordering areas of host brain, possibly indicating a defective graft-host barrier. Taken together, these results show that human cortical tissue pieces grafted to cortical cavities of immunosuppressed rats survive grafting and develop, and that reciprocal nerve fiber growth between grafts and hosts occur. Human cortical neurons can grow into the rat host brain in a pattern which is partly determined by host cortical architecture.
authors.affiliation: Department of Histology and Neurobiology, Karolinska Institute, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Humpel
authors.forename: M
authors.initials: M
authors.lastname: Bygdeman
authors.forename: L
authors.initials: L
authors.lastname: Olson
authors.forename: I
authors.initials: I
authors.lastname: Strömberg
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D016380:Brain Tissue Transplantation / Q000276:immunology / Q000502:physiology*; D002540:Cerebral Cortex / Q000276:immunology / Q000637:transplantation*; D005260:Female; D016332:Fetal Tissue Transplantation / Q000276:immunology / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D008938:Mitosis / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology*; D016900:Neurofilament Proteins / Q000276:immunology / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous / Q000276:immunology / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000276:immunology / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G; D016900:Neurofilament Proteins; D014446:Tyrosine 3-Monooxygenase