Striatal graft projections are influenced by donor cell type and not the immunogenic background

Kelly, Claire; Precious, Sophie Victoria; Penketh, Richard; Amso, Nazar Najib; Dunnett, Stephen B.; Rosser, Anne Elizabeth

doi:10.1093/brain/awm053

Cited by 38 publications

(34 citation statements)

References 24 publications

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“…Several studies have shown that cell survival is dependent on a number of factors. Kelly et al [26] determined that striatal graft survival is influenced more by the origin of the cells than the immunogenic background. Our study would appear to support this, since the absence of an immunogenic background in the NOD/SCID mice did not aid survival.…”

Section: Discussionmentioning

confidence: 99%

Long-term cultured human umbilical cord neural-like cells transplanted into the striatum of NOD SCID mice

Walczak¹,

Chen²,

Eve³

et al. 2007

Brain Research Bulletin

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The use of stem cells and other cells as therapies is still in its infancy. One major setback is the limited survival of the grafts, possibly due to immune rejection. Studies were therefore performed with human umbilical cord blood cells (HUCB) to determine the ability of these cells to survive in vivo and the effect of the immune response on their survival by transplantation into the normal striatum of immunodeficient NOD SCID mice.Long-term culture of HUCB cells resulted in several different populations of cells, including one that possessed fine processes and cell bodies that resembled neurons. Their neuronal phenotype was confirmed by immunohistochemical staining for the early neuronal marker TuJ1 and the potentially neural marker Nestin. Five days after cell transplantation of this neuronal phenotype, immunohistochemical staining for human mitochondria confirmed the presence of living HUCB cells in the mouse striatum, with cells localized at the site of injection, expressing early neural and neuronal markers (Nestin and TuJ1) as well as exhibiting neuronal morphology. However, no evidence of surviving cells was apparent 1 month postgrafting. The absence of signs of T cell-mediated rejection, such as CD4 and CD8 lymphocytes and minimal changes in microglia and astrocytes, suggest that cell loss was not due to a T cell-mediated immune response. In conclusion HUCB cells can survive long-term in vitro and undergo neuron-like differentiation. In mice, these cells do not survive a month. This may relate to the differentiated state of the cells transplanted into the unlesioned striatum, rather than T cell-mediated immunological rejection.

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Section: Discussionmentioning

confidence: 99%

Long-term cultured human umbilical cord neural-like cells transplanted into the striatum of NOD SCID mice

Walczak¹,

Chen²,

Eve³

et al. 2007

Brain Research Bulletin

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show abstract

“…Transplantation surgeries were performed as reported previously (Kelly et al, 2007(Kelly et al, , 2011 and are described in detail in the supplementary Materials and Methods. All animal experiments were performed in full compliance with the UK Animals (Scientific Procedures) Act 1986 and approved by local ethical review.…”

Section: Transplantationmentioning

confidence: 99%

Activin A directs striatal projection neuron differentiation of human pluripotent stem cells

et al. 2015

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The efficient generation of striatal neurons from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) is fundamental for realising their promise in disease modelling, pharmaceutical drug screening and cell therapy for Huntington's disease. GABAergic medium-sized spiny neurons (MSNs) are the principal projection neurons of the striatum and specifically degenerate in the early phase of Huntington's disease. Here we report that activin A induces lateral ganglionic eminence (LGE) characteristics in nascent neural progenitors derived from hESCs and hiPSCs in a sonic hedgehog-independent manner. Correct specification of striatal phenotype was further demonstrated by the induction of the striatal transcription factors CTIP2, GSX2 and FOXP2. Crucially, these human LGE progenitors readily differentiate into postmitotic neurons expressing the striatal projection neuron signature marker DARPP32, both in culture and following transplantation in the adult striatum in a rat model of Huntington's disease. Activin-induced neurons also exhibit appropriate striatal-like electrophysiology in vitro. Together, our findings demonstrate a novel route for efficient differentiation of GABAergic striatal MSNs from human pluripotent stem cells.

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“…Further to this, we have previously compared survival and axonal outgrowth of transplants of human primary foetal striatal tissue with short-term expanded (10 days) striatal FNPs, where we found richer cellular outgrowth from the FNP-derived grafts [58]. Recently, we have reported that striatal-derived FNPs expanded for short periods in culture prior to transplantation yield the same number of DARPP-32-positive neurons in grafts as those derived from primary foetal WGE [59].…”

Section: Alternative Donor Cell Sourcesmentioning

confidence: 83%

Transplantation in HD: Are We Transplanting the Right Cells?

Precious¹,

Kelly²

2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Cell replacement therapy is a viable option for the treatment of Huntington's disease (HD), where the aim is to replace the lost medium spiny projection neurons of the striatum. The intra-striatal engraftment of developing striatal precursors harvested from the foetal brain has provided proof of concept in both rodent models and human patients that these primary foetal tissue grafts can bring about a degree of functional recovery in a HDdegenerated brain. With the advent of pluripotent stem cell technologies, novel, potential alternative donor cell sources have become available. Ongoing studies are assessing the capacity of these cells to differentiate towards striatal precursors for transplantation in HD. Here, we review the characteristics of potential donor cells for HD with respect to available cell markers, functional properties and maturity of cells upon transplantation. We consider the optimal composition of the donor cell population, that is, whether a heterogeneous population containing all cell types from the developing striatum (the whole ganglionic eminence) is preferable to a more homogeneous population of striatal projection neurons, as directed by differentiation protocols applied to pluripotent stem cells. Furthermore, we consider what might be required to improve transplant efficacy and success, with respect to striatal differentiation of transplanted cells and functional improvement.

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Striatal graft projections are influenced by donor cell type and not the immunogenic background

Cited by 38 publications

References 24 publications

Long-term cultured human umbilical cord neural-like cells transplanted into the striatum of NOD SCID mice

Long-term cultured human umbilical cord neural-like cells transplanted into the striatum of NOD SCID mice

Activin A directs striatal projection neuron differentiation of human pluripotent stem cells

Transplantation in HD: Are We Transplanting the Right Cells?

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