Astrocyte-secreted GDNF and glutathione antioxidant system protect neurons against 6OHDA cytotoxicity

Sandhu, Jagdeep K.; Gardaneh, Mossa; Iwasiow, Rafal M.; Lanthier, Patricia; Gangaraju, Sandhya; Ribecco-Lutkiewicz, Maria; Tremblay, Roger; Kiuchi, Kazutoshi; Sikorska, Marianna

doi:10.1016/j.nbd.2008.11.016

Cited by 97 publications

(91 citation statements)

References 55 publications

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“…Of note, the expression of glial cell-derived neurotrophic factor (Gdnf), sonic hedgehog (Shh), and Fgf8 was greatly elevated in VM-Ast compared with Ctx-Ast or control Ctx-NPCs. GDNF has physiologic neurotrophic roles specific for mDA neurons (44), and SHH, by establishing an autoregulatory loop with Foxa2, is one of the most important factors in mDA neuron development and survival (45,46). The cooperative actions of FGF8 and SHH are critical for mDA neuron development (47), and thus, this cytokine combination is commonly used for in vitro mDA neuron patterning from stem cells (48,49).…”

Section: Resultsmentioning

confidence: 99%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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In this study, we have attempted to exploit the neurotrophic actions of astrocytes and Nurr1+Foxa2 functions in this cell type to improve the therapeutic outcomes of NPC transplantation using an animal model of PD. Our in vitro assays using a coculture system and conditioned media treatment revealed that astrocytes, especially those cultured from the ventral midbrain (VM), where HNF3β) is a potent cofactor that synergizes the Nurr1-mediated antiinflammatory roles in glia (16). Furthermore, forced coexpression of Nurr1 and Foxa2 (Nurr1+Foxa2) in glia promotes the synthesis and release of various neurotrophic factors, indicating that engineering of Nurr1 and Foxa2 in glia could become a powerful strategy for treating CNS disorders. Representative images of TH + DA neurons differentiated from VM-NPCs in the presence of Ctx-NPCs (control), Ctx-Ast, or VM-Ast. Scale bar: 100 μm. Insets, enlarged images of the boxed areas (original magnification, ×400). (C) DA neuronal yields at differentiation day 6 (D6). (D-H) Morphometric measurement of DA neuron maturity assessed by neurite outgrowth lengths (D), soma size (E), and by the Sholl test (F and G). In the Sholl analysis, the total number of neurite crossings was counted in each circle with the radius increasing in steps of 15 μm (F). The critical value (G) is the radius at which there was a maximum number of neurite crossings. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast, 1-way ANOVA. n = 3-5 wells (C) and 100 (D and E) and 25-30 (F and G) TH + cells in each group.(H) Representative TH + neuronal morphologies reconstructed in 3D by Neurolucida. (I-L) Synaptic densities on TH + fibers. (I) Representative confocal images of synapsin + TH + fibers. Scale bar: 25 μm. Puncta positive for the synaptic vesicle-specific markers SV2 (J), synapsin (K), and bassoon (L) on TH + fibers were counted. *P < 0.05, significantly different from the control; # P < 0.05, significantly different from Ctx-Ast. n = 20 TH + fibers for each group. (M) Presynaptic DA release. n = 3 independent cultures. DA levels were measured in the media conditioned in the differentiated cultures for 24 hours (D13-D15) and in cultures evoked by KCl-mediated depolarization for 30 minutes. *P < 0.05; # P < 0.05, 1-way ANOVA. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 6 5 jci.org Volume 128 Number 1 January 2018 (Supplemental Figure 1B; supplemental material available online with this article; https://doi.org/10.1172/JCI93924DS1), immunocytochemical analyses revealed that major cell populations in the Ctx-and VM-astroglial cultures at day in vitro (DIV) 14 were positive for GFAP (85% and 82%), CD44 (79% and 76 %), GLT-1 (58% and 71 %), and GLAST protein (71% and 77%), respectively (Supplemental Figure 1A), except S100β (20% and 32%), a soluble protein associated with harmful reactivation of astrocytes (22). A few (0.24% ± 0.35% in Ctx-Ast and 0.43% ± 0.39% in VM-Ast, where Ast indicates astrocytes) and none of the cells in these c...

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Section: Resultsmentioning

confidence: 99%

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Song¹,

Oh²,

Kwon³

et al. 2017

Journal of Clinical Investigation

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“…The first two are well known growth factors involved in both the differentiation of new neurons and the protection/survival of established differentiated cells [62,63]. In contrast, GDNF is particularly involved in the specific survival and differentiation of dopaminergic neurons [64,65]. Moreover, the expression of the genes encoding these factors was potentiated whenever EFG/FGF-2 were present in the medium.…”

Section: Central Nervous Systemmentioning

confidence: 99%

Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine

Salgado

Reis²,

Sousa³

et al. 2010

CSCR

529

217

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Stem cells have been long looked at as possible therapeutic vehicles for different health related problems. Among the different existing stem cell populations, Adipose derived Stem Cells (ASCs) have been gathering attention in the last 10 years. When compared to other stem cells populations and sources, ASCs can be easily isolated while providing higher yields upon the processing of adipose tissue. Similar to other stem cell populations, it was initially thought that the main potential of ASCs for regenerative medicine approaches was intimately related to their differentiation capability. Although this is true, there has been an increasing body of literature describing the trophic effects of ASCs on the protection, survival and differentiation of a variety of endogenous cells/tissues. Moreover, they have also shown to possess an immunomodulatory character. This effect is closely related to the ASCs' secretome and the soluble factors found within it. Molecules such as hepatocyte growth factor (HGF), granulocyte and macrophage colony stimulating factors, interleukins (ILs) 6, 7, 8 and 11, tumor necrosis factor-(TNF-), vascular endothelial growth factor (VEGF), brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), adipokines and others have been identified within the ASCs' secretome. Due to its importance regarding future applications for the field of regenerative medicine, we aim, in the present review, to make a comprehensive analysis of the literature relating to the ASCs' secretome and its relevance to the immune and central nervous system, vascularization and cardiac regeneration. The concluding section will highlight some of the major challenges that remain before ASCs can be used for future clinical applications.

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“…In postmortem PD patients, biochemical analysis and immunostaining results showed that the levels of neurotrophic factors such as glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) were decreased (55). Interestingly, supplementation with glial-derived growth factors such as GDNF (56,57), BDNF (58,59) and mesencephalic astrocytederived neurotrophic factor (MANF) (60) protected DA neurons from neurotoxins (6-OHDA, MPP + and H2O2). Although the relationship between reactive astrocytes and the expression of neurotrophic factors is unknown, these results suggest that decreased levels of astrocyte-derived neurotrophic factors are at least somewhat responsible for DA neuronal death in PD.…”

Section: Reactive Astrocytes In Pdmentioning

confidence: 99%

The role of neuroinflammation on the pathogenesis of Parkinson's disease

Chung¹,

Ko²,

Bok³

et al. 2010

BMB Reports

141

124

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Astrocyte-secreted GDNF and glutathione antioxidant system protect neurons against 6OHDA cytotoxicity

Cited by 97 publications

References 55 publications

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Cografting astrocytes improves cell therapeutic outcomes in a Parkinson’s disease model

Adipose Tissue Derived Stem Cells Secretome: Soluble Factors and Their Roles in Regenerative Medicine

The role of neuroinflammation on the pathogenesis of Parkinson's disease

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