Genetically Modified Neural Stem Cells for a Local and Sustained Delivery of Neuroprotective Factors to the Dystrophic Mouse Retina

Jung, Gila; Sun, Jing; Petrowitz, Bettina; Riecken, Kristoffer; Kruszewski, Katharina; Jankowiak, Wanda; Kunst, Frank; Skevas, Christos; Richard, Gisbert; Bartsch, Udo

doi:10.5966/sctm.2013-0013

Cited by 30 publications

(41 citation statements)

References 54 publications

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“…); (iii) not only the potential to differentiate may be changed during culture, but also the factors these cells secrete could differ depending on the pretreatment, the origin, or the differentiation state; (iv) transplantation of stem cells could modulate the immune system and therefore act indirectly on the CNS; and (v) stem cells can also be used as vehicle: for example, genetically modified stem cells stably deliver neurotrophic or other factors to damaged tissue, e.g., CNTF (Jung et al, 2013). …”

Section: Potential Effects Of Endogenous and Transplanted Stem Cells mentioning

confidence: 99%

Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage

Roll

Faissner

2014

Front. Cell. Neurosci.

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The limited regeneration capacity of the adult central nervous system (CNS) requires strategies to improve recovery of patients. In this context, the interaction of endogenous as well as transplanted stem cells with their environment is crucial. An understanding of the molecular mechanisms could help to improve regeneration by targeted manipulation. In the course of reactive gliosis, astrocytes upregulate Glial fibrillary acidic protein (GFAP) and start, in many cases, to proliferate. Beside GFAP, subpopulations of these astroglial cells coexpress neural progenitor markers like Nestin. Although cells express these markers, the proportion of cells that eventually give rise to neurons is limited in many cases in vivo compared to the situation in vitro. In the first section, we present the characteristics of endogenous progenitor-like cells and discuss the differences in their neurogenic potential in vitro and in vivo. As the environment plays an important role for survival, proliferation, migration, and other processes, the second section of the review describes changes in the extracellular matrix (ECM), a complex network that contains numerous signaling molecules. It appears that signals in the damaged CNS lead to an activation and de-differentiation of astrocytes, but do not effectively promote neuronal differentiation of these cells. Factors that influence stem cells during development are upregulated in the damaged brain as part of an environment resembling a stem cell niche. We give a general description of the ECM composition, with focus on stem cell-associated factors like the glycoprotein Tenascin-C (TN-C). Stem cell transplantation is considered as potential treatment strategy. Interaction of transplanted stem cells with the host environment is critical for the outcome of stem cell-based therapies. Possible mechanisms involving the ECM by which transplanted stem cells might improve recovery are discussed in the last section.

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Section: Potential Effects Of Endogenous and Transplanted Stem Cells mentioning

confidence: 99%

Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage

Roll

Faissner

2014

Front. Cell. Neurosci.

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“…Immunohistochemical analyses were performed as described. 37,38 In brief, central (i.e., in the plane of the optic disc) retina sections were blocked in PBS containing 0.1% bovine serum albumin and 0.3% Triton X-100 (TX-100; both from Sigma-Aldrich, Deisenhofen, Germany), incubated with primary antibodies (Table) overnight at room temperature, washed in PBS, and incubated with Cy3-conjugated secondary antibodies (1:200; all from Jackson Immunoresearch Laboratories, West Grove, PA, USA) overnight. Cone photoreceptors were visualized by incubating sections with biotinylated peanut agglutinin (PNA; 1:5000; Vector Laboratories, Burlingame, CA, USA) followed by Cy3-conjugated streptavidin (1:500; Jackson Immunoresearch Laboratories).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Photoreceptor numbers were determined in central retina sections by counting DAPI-stained photoreceptor cell nuclei encircled by recoverin-immunoreactivity in three equidistant areas between the optic disc and the peripheral margin of the temporal and nasal retina, respectively, each covering the outer nuclear layer over a length of 220 lm. 37 The total number of photoreceptor cells in the six retina areas was calculated for six animals of each genotype and developmental age. Numbers of PNA-positive cones were determined in 4-month-old Cln7 KO and age-matched wild-type mice on photomicrographs taken from central retina sections at both sides of the optic disc.…”

Section: Determination Of Retina and Outer Nuclear Layer Thickness Anmentioning

confidence: 99%

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neuronal ceroid lipofuscinoses comprise a genetically heterogeneous group of mainly childhood-onset neurodegenerative lysosomal storage disorders. Progressive loss of vision is among the typical clinical symptoms of these fatal disorders. Here, we performed a detailed analysis of retinal degeneration in mice deficient in the lysosomal membrane protein CLN7, a novel animal model of CLN7 disease.METHODS. Immunohistochemical analyses of retinas at different ages were performed to qualitatively and quantitatively characterize retinal degeneration in CLN7-deficient mice. Storage material in mutant retinas was analyzed by electron microscopy, and expression levels of various lysosomal proteins were studied using immunohistochemistry, immunoblot analyses, and quantitative real-time PCR.RESULTS. We observed an early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice, resulting in the loss of more than 70% rod photoreceptors in 4-month-old animals. The number of cone photoreceptors was not detectably altered at this age. Loss of rod photoreceptors was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas. We also found a marked dysregulation of various lysosomal proteins in mutant retinas. CONCLUSIONS.We conclude that the retina of CLN7-deficient mice represents a useful model to elucidate the pathomechanisms ultimately leading to neurodegeneration in CLN7 disease, and to evaluate the efficacy of strategies aimed at developing treatments for this fatal neurodegenerative lysosomal storage disorder.

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“…Far from being science fiction, researchers can genetically modify (stem) cells to make them produce more growth factors or proteins of interest, as Trojan horses to deliver molecules to specific CNS locations. For instance, NSCs engineered to overexpress CNTF exert neuroprotection by in situ differentiation into supportive astrocytes in a mouse model of photoreceptor degeneration [176] . Similarly, NSCs overexpressing nerve growth factor showed beneficial effects on cognitive functions after CNS transplantation and astrocyte differentiation in a learning deficit mouse model [177] .…”

Section: Directionsmentioning

confidence: 99%

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Nicaise

Mitrečić

Falnikar

et al. 2015

WJSC

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in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology. Core tip: Amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) result in incurable neurological dysfunction due to loss of spinal motor neurons and axonal degeneration, amongst other mechanisms. Astrocytes are increasingly recognized as being necessary for neuroprotection and regeneration in the central nervous system as they promote axonal growth and deliver essential neurotrophic factors under both physiological and pathophysiological conditions. Given the central role played by astrocytes, we gathered convincing results from ALS and SCI literature that argue in favor of stem cell-based astrocyte replacement therapies and stress the scientific community to investigate more deeply the molecular understanding of astrocyte biology. MULTIPLE FACETS OF ASTROCYTES IN THE CENTRAL NERVOUS SYSTEM Astrocyte functionsAstrocytes are the most abundant cells in the central nervous system (CNS), outnumbering neuronal cells by several fold in some CNS regions. They have long been relegated to a secondary position, behind neurons or oligodendrocytes, as many thought that astrocytes were barely by-standers of the CNS. Accounting for a large fraction of the brain volume, their particular shape and tissue distribution are known to elaborate an extensive network of fine interconnected processes. Their star-shaped morphology projecting long branched processes provides a large coverage of CNS structures and the ensheathment of the brain or spinal cord in the pia matter. They draw the whole brain microanatomy by secreting astrocyte-derived extracellular matrix proteins (e.g., chondroitin sulfate proteoglycans, hyaluronan, tenascin proteins family, thrombospondin), thereby providing structural support for nervous system cells. Beside their structural role, astrocytes are recognized to fulfill and support many, if not all, functions of the healthy CNS [1] . Astrocyte endfeet cover more than 90% of the CNS vasculature and come in contact with endothelial cells. Expressing key glucose transporter-1, astrocytes convoy glucose from blood vessels to nervous system cells, most of them being devoid of direct access to this high-end source of energy. Hence, astrocytes synthetize via specific metabolic pathways glycogen and lactate, main energy fuels for neurons or distant synapses. Through humoral factors released at the perivascular space, astrocytes control local cerebral blood flow and bloodbrain barrier (BBB) integrity. Transforming growth factor-beta, glial-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2) and angiopoietin 1 (binding the endothelium-specific receptor TIE2), all secreted at the vascular end-feet, act on endothelial cells in order to induce or maintain an operational BBB [2,3] . Astrocytes-released growth factors [e.g., brainderived neurotrophic factor, BDNF; ciliary neurotrophic factor (CNTF)] exert beneficial effects far beyond the perivascular spa...

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Genetically Modified Neural Stem Cells for a Local and Sustained Delivery of Neuroprotective Factors to the Dystrophic Mouse Retina

Cited by 30 publications

References 54 publications

Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage

Influence of the extracellular matrix on endogenous and transplanted stem cells after brain damage

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

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