Striatal allografts in patients with Huntington’s disease: impact of diminished astrocytes and vascularization on graft viability

Abstract

Neuronal transplantation has been proposed as a potential therapy to replace lost neurons in Huntington's disease. Transplant vascularization and trophic support are important for graft survival. However, very few studies have specifically addressed graft vascularization in patients with neurological disorders. In the present study, we analysed the vasculature of the host putamen and solid grafts of foetal striatal tissue transplanted into patients with Huntington's disease 9 and 12 years previously. Grafts were characterized by a significantly reduced number of large calibre blood vessels in comparison with the host brain. There were also significantly fewer astrocytes and gap junctions, suggesting a lack of functional blood-brain barrier components within the grafted tissue. Additionally, grafts demonstrated a nearly complete absence of pericytes (compared with the striatum) that are considered important for vascular stabilization and angiogenesis. Finally, the host striatum had a marked increase in atrophic astrocytes in comparison with controls and grafts. The extent to which the lower number of large calibre vessels and astrocytes within the transplants contributed to suboptimal graft survival is unknown. The marked increase in atrophic astrocytes in the host brain surrounding the grafts suggests that reduced host trophic support may also contribute to poor graft survival in Huntington's disease. A better understanding of the way in which these components support allografted tissue is critical to the future development of cell-based therapies for the treatment of Huntington's disease.

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

“…Treating HD by transplanting solid fetal striatal tissue has been tested (Cisbani et al, 2013). The striatal grafts displayed significantly reduced numbers of large blood vessels and astrocytes, which may have contributed to the poor graft survival.…”

Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development

“…Furthermore, histological studies in brain samples from HD patients, who had been transplanted with fetal striatal primordial tissue approximately 1 decade earlier to die, revealed a marked increase in atrophic astrocytes in the host brain surrounding the grafts, suggesting that a deficiency in host growth factors support, secreted by glia, may exacerbate the striatal neurons degeneration in HD (Cicchetti et al, 2011;Cisbani et al, 2013). So, in addition to the glutamate excitotoxicity theory for HD pathogenesis, a defective expression or activity of neurotrophic factors, such as BDNF and GDNF factors, may contribute to neuronal damage in HD (Giralt et al, 2010;Sarchielli et al, 2014;Wang et al, 2012;Zuccato et al, 2001;Zuccato et al, 2008).…”

Transplantation in HD: Are We Transplanting the Right Cells?

“…One post-mortem study from the Florida trial, 10-year post-transplantation, demonstrated graft survival with expression of markers of striatal projection neurons and interneurons and evidence of synaptic connections between transplanted neurons and host-derived dopaminergic and glutamatergic neurons, but also suggested some degeneration of grafted neurons [22]. A further post-mortem analysis from the Florida cohort, up to 12-year post-transplantation, observed that there were both fewer blood vessels and fewer astrocytes in the graft compared with the surrounding host tissue, which together may result in reduced trophic support to the graft and impact on graft survival [23]. However, these grafts also showed some typical striatal graft morphology in which there were regions of the grafts that were positive for AChE, termed p-zones, as well as areas with no expression of AChE, termed non-p-zones [23].…”

“…A further post-mortem analysis from the Florida cohort, up to 12-year post-transplantation, observed that there were both fewer blood vessels and fewer astrocytes in the graft compared with the surrounding host tissue, which together may result in reduced trophic support to the graft and impact on graft survival [23]. However, these grafts also showed some typical striatal graft morphology in which there were regions of the grafts that were positive for AChE, termed p-zones, as well as areas with no expression of AChE, termed non-p-zones [23].…”

“…In addition to the clinical data discussed above, there are a number of published reports of post-mortem analyses from these transplant trials [13,[19][20][21][22][23]. The earliest post-mortem time was 6-month post-transplantation [13], and in this study, the authors reported graft-derived DARPP-32 (dopamine-and cyclic-AMP-regulated phosphoprotein of molecular weight 32 kDa), NeuN, calretinin, somatostatin and GFAP, as well as graft innervation of host-derived tyrosine hydroxylase fibres.…”