Photoreceptor Protection by Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF)

Lü, Jin-Chun; Luo, Lan; Huang, Dan; Liu, Xian; Xia, Xin; Wang, Zhengying; Lam, Byron L.; Yi, Jinglin; Wen, Rong; Li, Yiwen

doi:10.1523/eneuro.0109-18.2018

Cited by 23 publications

(19 citation statements)

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“…Our data provide a link between a miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PDGF-AA pathway, via miR-30a*, inﬂuences XBP1-mediated MANF expression in the UPR. To date, the receptor and the signaling pathway for MANF are still obscure[ 56 ], although protein kinase C signaling has been activated downstream of MANF[ 57 ]. Therefore, how MANF functions in a paracrine manner to induce M2 polarization needs further attention and investigation.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Yang¹,

Li²,

Qu³

et al. 2020

WJSC

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BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced brain repair. However, the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear. Recent evidence suggests that mesencephalic astrocyte–derived neurotrophic factor (MANF) and platelet-derived growth factor-AA (PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization. AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization. METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression. Using a rat middle cerebral artery occlusion (MCAO) model transplanted by BMSCs and BMSCs–microglia Transwell coculture system, the effect of BMSCs-induced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence. Additionally, microglia were transfected with mimics of miR-30a*, which inﬂuenced expression of X-box binding protein (XBP) 1, a key transcription factor that synergized with activating transcription factor 6 (ATF6) to govern MANF expression. We examined the levels of miR-30a*, ATF6, XBP1, and MANF after PDGF-AA treatment in the activated microglia. RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production, but increased M1 marker expression in vivo or in vitro . Furthermore, PDGF-AA treatment decreased miR-30a* expression, had no influence on the levels of ATF6, but enhanced expression of both XBP1 and MANF. CONCLUSION BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.

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Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Yang¹,

Li²,

Qu³

et al. 2020

WJSC

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“…Granules of each fraction were fixed with 2.5% glutaraldehyde and 2% paraformaldehyde overnight, followed by 1% OsO 4 for 1 h. Fixed samples were dehydrated, embedded in an Epon/Araldite mixture [33], sectioned at 1 µm thickness, and examined by DIC light microscopy without staining.…”

Section: Morphological Analysismentioning

confidence: 99%

A2E Distribution in RPE Granules in Human Eyes

Guan

Jiao

et al. 2020

Molecules

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A2E (N-retinylidene-N-retinylethanolamine) is a major fluorophore in the RPE (retinal pigment epithelium). To identify and characterize A2E-rich RPE lipofuscin, we fractionated RPE granules from human donor eyes into five fractions (F1–F5 in ascending order of density) by discontinuous sucrose density gradient centrifugation. The dry weight of each fraction was measured and A2E was quantified by liquid chromatography/mass spectrometry (LC/MS) using a synthetic A2E homolog as a standard. Autofluorescence emission was characterized by a customer-built spectro-fluorometer system. A significant A2E level was detected in every fraction, and the highest level was found in F1, a low-density fraction that makes up half of the total weight of all RPE granules, contains 67% of all A2E, and emits 75% of projected autofluorescence by all RPE granules. This group of RPE granules, not described previously, is therefore the most abundant RPE lipofuscin granule population. A progressive decrease in autofluorescence was observed from F2 to F4, whereas no autofluorescence emission was detected from the heavily pigmented F5. The identification of a novel and major RPE lipofuscin population could have significant implications in our understanding of A2E and lipofuscin in human RPE.

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“…Overexpression of MANF ameliorates the loss of Purkinje cells in a mouse model of spinocerebellar ataxia (Yang et al, 2014) and promotes neural progenitor cells migration and differentiation in a rat cortical stroke model (Tseng et al, 2017a). In addition, MANF is also reported to facilitate retinal ganglion cells and photoreceptor cells regeneration in the retina by regulating neuroinflammation and immune response (Neves et al, 2016;Gao et al, 2017;Lu et al, 2018). Similarly, CDNF has also been reported to be neuroprotective in animal models of PD, AD, and periphery nerve injury (Lindholm et al, 2007;Cheng et al, 2013;Kemppainen et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Wen

Wang

et al. 2020

Front. Mol. Neurosci.

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Neurite outgrowth is essential for brain development and the recovery of brain injury and neurodegenerative diseases. In this study, we examined the role of the neurotrophic factor MANF in regulating neurite outgrowth. We generated MANF knockout (KO) neuro2a (N2a) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and demonstrated that MANF KO N2a cells failed to grow neurites in response to RA stimulation. Using MANF siRNA, this finding was confirmed in human SH-SY5Y neuronal cell line. Nevertheless, MANF overexpression by adenovirus transduction or addition of MANF into culture media facilitated the growth of longer neurites in RA-treated N2a cells. MANF deficiency resulted in inhibition of Akt, Erk, mTOR, and P70S6, and impaired protein synthesis. MANF overexpression on the other hand facilitated the growth of longer neurites by activating Akt, Erk, mTOR, and P70S6. Pharmacological blockade of Akt, Erk or mTOR eliminated the promoting effect of MANF on neurite outgrowth. These findings suggest that MANF positively regulated neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways.

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Photoreceptor Protection by Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF)

Cited by 23 publications

References 50 publications

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

A2E Distribution in RPE Granules in Human Eyes

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

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