The fate of human glial cells following transplantation in normal rodents and rodent models of neurodegenerative disease

Pundt, Lisa L.; Kondoh, Takeshi; Low, Walter C.

doi:10.1016/0006-8993(95)00753-d

Cited by 29 publications

(19 citation statements)

References 31 publications

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“…Fetal asttocytes are easily purified and have been shown to survive following ttansplantation into the rat brain (Cunningham et al, 1991a(Cunningham et al, , 1994Yoshimoto et al, 1995). In addition, extensive migration and smvival have been shown for human fetal gUal ceUs grafted into rat brain (Pundt et al, 1995), suggesting that ttansgene product might be deUvered to a wider area with the use of human fetal asttocytes.…”

Section: Discussionmentioning

confidence: 98%

Human Fetal Astrocytes as anEx VivoGene Therapy Vehicle for Delivering Biologically Active Nerve Growth Factor

Lin¹,

Cunningham²,

Epstein³

et al. 1997

Human Gene Therapy

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The therapeutic use of neurotrophic factors for neurodegenerative diseases is promising, however, optimal methods for continuous delivery of these substances to the human central nervous system (CNS) remains problematic. One approach would be to graft genetically engineered human cells that continuously secrete high levels of a biologically produced and processed neurotrophic factor. This ex vivo gene therapy approach has worked well in animal models of neurodegenerative diseases using a variety of nonneuronal cell types to deliver the transgene. In our studies, we have been investigating the potential of astrocytes, a cell type normally present in the CNS, as a vehicle for ex vivo gene therapy. Here, we demonstrate that astrocytes in the human fetal cortex can be isolated and efficiently infected with an amphotropic retrovirus harboring mouse beta-nerve growth factor (NGF). These transduced astrocytes express high levels of NGF mRNA and secrete bioactive NGF protein as demonstrated by stimulation of neurite outgrowth from adrenal chromaffin cells. NGF ELISA showed that these astrocytes secrete NGF protein at a rate of 41 ng/day per 10(5) cells after 2 weeks in vitro, whereas NGF is undetectable in medium conditioned by normal astrocytes. These data suggest that human fetal astrocytes can be used for delivering biologically produced neurotrophic factors to the human CNS.

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Section: Discussionmentioning

confidence: 98%

Human Fetal Astrocytes as anEx VivoGene Therapy Vehicle for Delivering Biologically Active Nerve Growth Factor

Lin¹,

Cunningham²,

Epstein³

et al. 1997

Human Gene Therapy

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show abstract

“…The interest in human astrocytes has been growing (Yong et al, 1991(Yong et al, , 1992Aloisi et al, 1992;Perzelova and Mares, 1993;Pundt et al, 1995;Lin et al, 1997). Yong and colleagues (1992) reported that up to 80% of the primary cultured cells were macrophages/microglial cells.…”

Section: Discussionmentioning

confidence: 96%

“…In contrast, primary cultured cells are more suitable. One of the best cell types for ex vivo gene transfer and subsequent transplantation may be astrocytes (La Gamma et al, 1993;Castillo et al, 1994;Cunningham et al, 1994;Ridoux et al, 1994;Pundt et al, 1995;Lundberg et al, 1996;Lin et al, 1997), which are normally present in the CNS as the major supporting cells with efficient secretion machinery. Grafted astrocytes, previously modified to produce enzymes, neurotransmitters or trophic factors, can integrate and function suitably in the CNS (see references in Taylor, 1997).…”

Section: Discussionmentioning

confidence: 98%

“…Several cell types, e.g., progenitor cells, neurons, glial cells, fibroblasts, and myoblasts (Wolff et al, 1989;Horellou et al, 1990a,b;Fisher et al, 1991;Fisher and Gage, 1993;Gage et al, 1995;Sabate et al, 1995;Fisher, 1997;Martinez-Serrano and Bjorklund, 1997), have been investigated as vehicles for gene delivery to the central nervous system (CNS). Particular attention has been paid to the therapeutic potential of genetically engineered astrocytes (Cunningham et al, 1991(Cunningham et al, , 1994La Gamma et al, 1993;Castillo et al, 1994;Pundt et al, 1995;Lundberg et al, 1996;Lin et al, 1997). Astrocytes may be especially useful for brain repair: they are normal CNS constituents endowed with efficient secretory mechanisms and provide support to neurons through the release of trophic factors that promote their survival, differentiation, and regeneration.…”

Section: Introductionmentioning

confidence: 97%

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Toward Autologous ex Vivo Gene Therapy for the Central Nervous System with Human Adult Astrocytes

Ridet

Corti²,

Pencalet³

et al. 1999

Human Gene Therapy

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The combination of gene transfer techniques and cell transplantation is a promising approach to deliver therapeutic molecules into the CNS. To optimize gene transfer systems, several neural and nonneural cell types are currently under investigation. Among these cells, astrocytes are particularly well suited because of their CNS origin, their efficient secretory mechanisms, and their role as neuronal support. Most importantly, the use of human adult astrocytes as cellular vehicles for ex vivo gene transfer may open the way to autologous transplantation, thus obviating immunological rejection and the side effects of immunosuppressors. In the present study, we report the ability of these cells to be expanded and genetically modified in vitro. Astrocytes derived from human adult cerebral cortex were grown and maintained in vitro as pure primary cultures for at least 10 months. In addition, cells were efficiently transduced by an adenoviral vector encoding human tyrosine hydroxylase (hTH) under the negative control of the tetracycline-based regulatory system (tet-off). The infected cells synthesized large amounts of active hTH and released L-dopa. In addition, doxycycline, a potent analog of tetracycline, efficiently regulated transgene expression. This work is a first step toward the development of therapeutic strategies based on the use of genetically engineered human adult astrocytes for autologous transplantation in human neurodegenerative diseases and CNS trauma.

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“…Whether the massive rostral migration observed in our experimental paradigm was due to specific chemotactic signals released from the lesion site or represented a nonspecific gradient of migration, this property could be exploited for the delivery of endogenous or exogenous molecules close to the transection site to promote the permissiveness of the glial scar and axonal regeneration. Previous studies have shown that nonmodified neonatal astrocytes transplanted to the hemisected rat spinal cord can induce a rapid and significant reduction of the host glial scar tissue around the lesion site (Pundt et al, 1995). Astrocytes transplanted to the injured nervous system may thus behave similarly to endogenous astrocytes during brain development by secreting trophic factors and playing multiple roles in axonal growth.…”

Section: Discussionmentioning

confidence: 99%

Integration of genetically modified adult astrocytes into the lesioned rat spinal cord

et al. 2006

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Combination of ex vivo gene transfer and cell transplantation is now considered as a potentially useful strategy for the treatment of spinal cord injury. In a perspective of clinical application, autologous transplantation could be an option of choice. We analyzed the fate of adult rat cortical astrocytes genetically engineered with a lentiviral vector transplanted into a lesioned rat spinal cord. Cultures of adult rat cortical astrocytes were infected with an HIV-1-derived vector (TRIP-CMV-GFP) and labeled with the fluorescent dye Hoechst. Transfected and labeled astrocyte suspension was injected at T11 in rats in which spinal cord transection at T7-T8 levels had been carried out 1 week earlier. Six weeks after grafting, the animals were sacrificed and transplants were retrieved either by Hoechst fluorescence or by immunohistochemistry for detection of glial fibrillary acidic protein (GFAP) and vimentin. Grafted astrocytes expressing green fluorescent protein (GFP) were found both at the injection and transection sites. Genetically modified astrocytes thus survived, integrated, and migrated within the host parenchyma when grafted into the completely transected rat spinal cord. In addition, they retained some ability to express the GFP transgene for at least 6 weeks after transplantation. Adult astrocytes infected with lentiviral vectors can therefore be a valuable tool for the delivery of therapeutic factors into the lesioned spinal cord.

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The fate of human glial cells following transplantation in normal rodents and rodent models of neurodegenerative disease

Cited by 29 publications

References 31 publications

Human Fetal Astrocytes as anEx VivoGene Therapy Vehicle for Delivering Biologically Active Nerve Growth Factor

Human Fetal Astrocytes as anEx VivoGene Therapy Vehicle for Delivering Biologically Active Nerve Growth Factor

Toward Autologous ex Vivo Gene Therapy for the Central Nervous System with Human Adult Astrocytes

Integration of genetically modified adult astrocytes into the lesioned rat spinal cord

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