Vascularization and Blood Brain Barrier Development

The next challenge in the survival of a healthy graft is the development of functional vascularization and a blood-brain barrier (BBB). The origin of angiogenesis in fetal brain grafts is still disputed. There is evidence that donor-derived vasculature already contained in the implanted tissue fragments can survive and rapidly develop connectivity with the host. When cell suspensions were used for allo- and xenografting, the BBB also appeared to form relatively soon and did not seem to be affected by concomitant treatments with CsA. These results were further confirmed, and additional findings suggest that early vascularization is determined intrinsically by the graft, possibly through locally produced growth factors (discussed later in the article).

Contrary to these reports, Geny et al. found that angiogenesis in the human fetal grafts is a much slower process, including a delayed redifferentiation of the endothelial cells present in the graft at the time of implantation, a phenomenon possibly dependent on the maturation of the fetal neuroglial tissue. Adding another twist to this debate, Pennel and Streit proposed that their studies with rat fetal allografts demonstrated early vascularization, but this was directly dependent on graft colonization by donor-derived microglia. In another similar study, Rostaing-Rigattieri et al. showed that not only microglia but also host-reactive astroglia and endothelial cells infiltrated the graft and participated in the reorganization of its cytoarchitecture. Finally, pilot studies in our lab showed that, in human fetal xenografts, the early development of a BBB, facilitated by in vitro manipulations before implantation, is crucial for long-term donor neuronal survival and differentiation.

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