Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington′s Disease

Sanberg, Paul R.; Giòrdano, Magda; Henault, Mark A.; Nash, David R.; Ragozzino, Michael E.; Hagenmeyer-Houser, Starr H.

doi:10.1155/np.1989.23

Cited by 28 publications

(3 citation statements)

References 28 publications

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“…To determine if the in vitro produced human GABA neurons exhibit functional properties of GABA MSNs and if they possess therapeutic potential for HD, we transplanted the LGE-like progenitors (maintained in suspension culture for 40 days), into the striatum of immune deficient SCID mice lesioned by QA, a model commonly used for testing efficacy of donor cells (Sanberg et al, 1989). Spinal GABA neural progenitors, which generated a similar proportion of GABA neurons in vitro, were used as a control.…”

Section: Resultsmentioning

confidence: 99%

Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

et al. 2012

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Degeneration of medium spiny GABA neurons in the basal ganglia underlies motor dysfunction in Huntington’s disease (HD) which presently lacks effective therapy. In this study, we have successfully directed human embryonic stem cells (hESCs) to enriched populations of DARPP32-expressing forebrain GABA neurons. Transplantation of these human forebrain GABA neurons and their progenitors, but not spinal GABA cells, into the striatum of quinolinic acid-lesioned mice results in generation of large populations of DARPP32+ GABA neurons, which project to the substantia nigra as well as receiving glutamatergic and dopaminergic inputs, corresponding to correction of motor deficits. This finding raises hopes for cell therapy for HD.

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Section: Resultsmentioning

confidence: 99%

Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

et al. 2012

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“…Transplants of primary striatal tissue, i.e. developing striatal cells that have been dissected from the embryonic ganglionic eminences, currently provide the best source of cells to replace degenerating striatal projection neurons both in animal models of Huntington's disease (HD) (Isacson et al ., 1986; Giordano et al ., 1988; Norman et al ., 1988; Sanberg et al ., 1989; Wictorin, 1992; Björklund et al ., 1994; Fricker et al ., 1997b; Kendall et al ., 1998; Watts et al ., 2000) and now in clinical trials (Bachoud‐Lévy et al ., 2000; Rosser et al ., 2002). Experiments transplanting embryonic striatal neurons/neuroblasts to rat models of Huntington's disease show that these striatal transplants provide good numbers of striatal projection neurons (DiFiglia et al ., 1988; Graybiel et al ., 1989; Zhou et al ., 1989; Clarke & Dunnett, 1990; Xu et al ., 1992; Campbell et al ., 1995).…”

Section: Introductionmentioning

confidence: 99%

Striatal neurons in striatal grafts are derived from both post‐mitotic cells and dividing progenitors

Fricker-Gates

White

Gates

et al. 2004

Eur J of Neuroscience

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Transplants of embryonic striatal tissue are characteristically heterogeneous, containing patches (P-zones) of striatal medium spiny projection neurons. It is not yet known how this morphology develops, and whether the striatal neurons in the grafts are derived from post-mitotic neuroblasts in the embryonic brain or from striatal progenitors that continue to divide after transplantation. To address this question we labelled dividing cells in the transplants with bromodeoxyuridine (BrdU), either prior to or after transplantation into the adult lesioned rat striatum. Cells for transplantation were either pre-labelled in utero by intraperitoneal (i.p.) injections of BrdU, or post-labelled after transplantation by i.p. injections to the hosts. Either two or six months after transplantation the brains were processed using double immunohistochemical techniques to detect BrdU and calbindin-positive neurons in the transplants. In the transplants pre-labelled with BrdU, approximately 30% of calbindin-positive cells were heavily labelled with BrdU, suggesting these had undergone a final division prior to transplantation. In transplants where cells had been labelled post-transplantation, approximately 17% of calbindin cells were heavily BrdU labelled. These results suggest that whereas a proportion of striatal medium spiny neurons in the striatal grafts were post-mitotic at the time of transplantation, other striatal progenitor cells can continue to divide after transplantation, and then complete an appropriate neuronal maturation programme in the adult host brain environment.

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“…To further examine hESC-derived MSNs in an adult and diseased environment, we stereotactically transplanted the same amount of LGE-like progenitors into the striatum of quinolinic acid (QA)-lesioned mice, which mimic some motor deficits of human HD ( Sanberg et al., 1989 ) ( Figure 6 A). These transplanted cells also gradually matured.…”

Section: Resultsmentioning

confidence: 99%

A Chemical Recipe for Generation of Clinical-Grade Striatal Neurons from hESCs

Zhang

et al. 2018

Stem Cell Reports

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SummaryDifferentiation of human pluripotent stem cells (hPSCs) into striatal medium spiny neurons (MSNs) promises a cell-based therapy for Huntington's disease. However, clinical-grade MSNs remain unavailable. Here, we developed a chemical recipe named XLSBA to generate clinical-grade MSNs from embryonic stem cells (ESCs). We introduced the γ-secretase inhibitor DAPT into the recipe to accelerate neural differentiation, and replaced protein components with small molecules. Using this optimized protocol we could efficiently direct regular human ESCs (hESCs) as well as clinical-grade hESCs to lateral ganglionic eminence (LGE)-like progenitors and striatal MSNs within less than half of the time than previous protocols (within 14 days and 21 days, respectively). These striatal cells expressed appropriate MSN markers and electrophysiologically acted like authentic MSNs. Upon transplantation into brains of neonatal mice or mouse model of Huntington's disease, they exhibited sufficient safety and reasonable efficacy. Therefore, this quick and highly efficient derivation of MSNs offers unprecedented access to clinical application.

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Intraparenchymal Striatal Transplants Required for Maintenance of Behavioral Recovery in an Animal Model of Huntington′s Disease

Cited by 28 publications

References 28 publications

Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

Human Embryonic Stem Cell-Derived GABA Neurons Correct Locomotion Deficits in Quinolinic Acid-Lesioned Mice

Striatal neurons in striatal grafts are derived from both post‐mitotic cells and dividing progenitors

A Chemical Recipe for Generation of Clinical-Grade Striatal Neurons from hESCs

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