title: Fetal liver-derived mesenchymal stem cell engraftment after allogeneic in utero transplantation into rabbits.
abstract: Prenatal transplantation of genetically engineered mesenchymal stem cells (MSCs) might benefit prevention or treatment of early-onset genetic disorders due to the cells' intrinsic regenerative potential plus the acquired advantage from therapeutic transgene expression. However, a thorough assessment of the safety, accessibility, and behavior of these MSCs in the fetal environment using appropriate animal models is required before we can advance toward a clinical application. We have recently shown that fetal rabbit liver MSCs (fl-MSCs) have superior growth rate, clonogenic capability, and in vitro adherence and differentiation abilities compared with adult rabbit bone marrow MSCs. In this follow-up study, we report safe and widespread distribution of recombinant pSF-EGFP retrovirus-transduced fl-MSCs (EGFP(+)-fl-MSCs) in neonatal rabbit tissues at 10 days after fetal allogeneic transplantation through both intrahepatic and intra-amniotic administration. Conversely, a more restricted biodistribution pattern according to the route of administration was apparent in the young rabbits intervened at 16 weeks after fetal EGFP(+)-fl-MSC transplantation. Furthermore, the presence of these cells in the recipients' tissues, tracked with the reporter provirus, was inversely related to the developmental stage of the fetuses at the time of intervention. Long-term engraftment was confirmed both by fluorescence in situ hybridization analysis on touch tissue imprints using a chromosome Y-specific BAC probe, and by immunohistochemical localization of EGFP expression. Finally, there was no evidence of immune responses against the transplanted EGFP(+)-fl-MSCs or the EGFP transgenic product in the treated young rabbits. Thus, cell transplantation approaches using genetically engineered fetal MSCs may prove particularly valuable to frontier medical treatments for congenital birth defects in perinatology.
authors.affiliation: Human Molecular Genetics Group, Institut d’Investigació Biomèdica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Moreno
authors.forename: Itziar
authors.initials: I
authors.lastname: Martínez-González
authors.forename: Marta
authors.initials: M
authors.lastname: Rosal
authors.forename: Marga
authors.initials: M
authors.lastname: Nadal
authors.forename: Jordi
authors.initials: J
authors.lastname: Petriz
authors.forename: Eduard
authors.initials: E
authors.lastname: Gratacós
authors.forename: Josep M
authors.initials: JM
authors.lastname: Aran
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D058948:Cell Tracking; D005260:Female; D005333:Fetus; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D017404:In Situ Hybridization, Fluorescence; D007267:Injections; D008099:Liver / Q000166:cytology* / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D011247:Pregnancy; D061251:Primary Cell Culture; D011817:Rabbits; D012190:Retroviridae; D014161:Transduction, Genetic; D019076:Transgenes; D014184:Transplantation, Homologous; D014599:Uterus
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins