Long-term delayed vascularization of human neural transplants to the rat brain

Abstract

Human neural transplants are being developed to treat Parkinson's disease. Previous characterization of human transplants focused on neuronal development, while little is known of the interaction between the transplant and its environment, among which blood is of prime importance. We evaluated here the formation of blood vessels in human neural xenografts placed into the brain of rats immunosuppressed with cyclosporin A. Using capillary wall markers, we found that human transplants remain virtually nonvascularized for more than 1 month. Angiogenesis takes place very slowly and the density of blood vessels is still quite poor after 3 months, the fine structure of these capillaries, when they form, is apparently normal. Functional studies indicate that the vascular network formed in the transplant allows blood circulation and exhibits a working barrier to macromolecules. Glucose uptake and consumption and cytochrome oxidase activity are almost undetectable up to 3 months after grafting. These results demonstrate that vascularization is much delayed in human xenografts into the rat brain. This delay is likely to be dependent on the maturation of the transplanted tissue. A dedifferentiation of human endothelial cells cotransplanted with neural cells occurs since histochemical and immunocytochemical markers revealing endothelial cells in the human fetus are not present up to 1 month in the transplant. The origin of this phenomenon is a matter of speculation. How neural cells survive and mature in such conditions are issues of prime interest for the future of human neural grafting.

Striatal progenitors derived from human ES cells mature into DARPP32 neuronsin vitroand in quinolinic acid-lesioned rats

“…The fact that cells replated in vitro from overgrown grafts differentiated normally into neurons and glia but failed to give rise to MSN, the neurogenesis time schedule of which had passed, is in agreement with this suggestion. It is interesting to mention that human-to-rat xenotransplantation of fetal GE tissue led to overgrowth (30) and that areas containing potentially proliferating cells were observed in grafts analyzed in a patient autopsied 18 months after grafting (25). Apparent overgrowth of human xenograft in rat brain may, therefore, only be a normal consequence of the physiological capacity of proliferation of human neural precursors, essentially revealed because of the size difference between rat and human brain.…”

Human ES cell-derived neural rosettes reveal a functionally distinct early neural stem cell stage

“…However, to rule out the possibility of ESC contribution completely, future studies should test in vivo growth potential in R-NSCs derived from primary CNS tissue (see below). Interestingly, neural overgrowth directly from primary CNS tissue has been reported in the past upon transplantation of human basal forebrain precursor into rodent models of Huntington's disease (Geny et al 1994). The propensity for continued rosette growth in vivo may have important implications in the context of recent studies reporting signs of neural overgrowth and spontaneous forebrain fates in vivo upon transplantation of ESC-derived dopamine neurons in rodent models of PD (Ferrari et al 2006;Roy et al 2006).…”

The Postischemic Environment Differentially Impacts Teratoma or Tumor Formation After Transplantation of Human Embryonic Stem Cell-Derived Neural Progenitors

“…Overgrowths have been reported in grafts from human fetal tissue 27 and from hESC-derived rosettes. 7,16,28,29 In our study, large grafts were exclusively neural composed of rosettes that generated impressive amounts of nestin-positive progenitors and Tuj1-positive neurons at the expenses of the host tissue.…”