Thrombospondin-4 Promotes Neuronal Differentiation of NG2 Cells via the ERK/MAPK Pathway

Yang, Hai Jie; Ping, Shuang; Ju, Fei; Zhang, Ya Ping; Li, Zhi Chao; Zhang, Bin-Bin; Lian, Jun Jiang; Wang, Lei; Cheng, Bin Feng; Wang, Mian; Feng, Zhi Wei

doi:10.1007/s12031-016-0845-1

Cited by 25 publications

(16 citation statements)

References 35 publications

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“…High levels of TSP-4 have been detected in remodeling and failing hearts [3][4][5][6][7] , several cancers [8][9][10][11][12][13] , and atherosclerotic lesions 14 . Recently, new functions have been ascribed to TSP-4 in the cardiovascular system [5][6][7][14][15][16][17][18][19][20][21][22][23][24][25] , cancer [8][9][10][11][12][24][25][26][27][28][29] , skeletal muscle 30,31 , and nervous system [32][33][34][35][36] , but effects of TSP-4 on cellular responses and the regulation of TSP-4 expression remain poorly understood. For example, with an exception of TGFbeta 25 , stimuli inducing TSP-4 expression in tissues remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…While TSP-4 is best known as a secreted extracellular matrix (ECM) protein, it became clear that some of its effects depend on its intracellular interactions: its binding to the ER lumenal domain of activating transcription factor 6α (Atf6α) protects cardiomyocytes from injury caused by ER stress responses 7 . Thus, this protein exerts its effect in multiple complementary ways: by initiating intracellular signaling and transiting through secretory pathways 38 , as well as by binding to its extracellular ligands and receptors upon secretion 5,6,14,24,30,33,37,[39][40][41][42][43][44][45][46][47][48] .…”

Section: Introductionmentioning

confidence: 99%

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Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

Rahman

Muppala

et al. 2020

Cell Death Dis

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Thrombospondin-4 (TSP-4) attracted renewed attention recently as a result of assignment of new functions to this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP-4 promotes local vascular inflammation in a mouse atherosclerosis model. A common variant of TSP-4, P387-TSP-4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP-4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages in more detail. We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture and in vivo in the model of LPS-induced peritonitis. In tissues and in cell culture, TSP-4 expression was associated with inflammation: TSP-4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFγ, GM-CSF, and LPS, induced TSP-4 expression in macrophages in vivo and in cell culture. Deficiency in TSP-4 in macrophages from Thbs4 −/− mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into a pro-inflammatory phenotype. Expression of TSP-4, especially more active P387-TSP-4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP-4 and reduced migration in presence of TSP-4, and these responses were further increased with P387 variant. We concluded that TSP-4 expression in macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP-4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP-4 was found to be the more active form of TSP-4 in all examined functions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

Rahman

Muppala

et al. 2020

Cell Death Dis

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“…High levels of TSP4 have been detected in remodeling and failing hearts [3][4][5][6][7], several cancers [8][9][10][11][12][13], and atherosclerotic lesions [14]. Recently, new functions have been ascribed to TSP4 in cardiovascular system [5][6][7][14][15][16][17][18][19][20][21][22][23][24][25], cancer [8][9][10][11][12][24][25][26][27][28][29], and nervous system [30][31][32][33][34], but effects of TSP4 on cellular responses and the regulation of TSP4 expression remain poorly understood. For example, with an exception of TGF-beta [25], stimuli inducing TSP4 expression in tissues remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Effect of Thrombospondin-4 on Pro-inflammatory Phenotype Differentiation and Apoptosis in Macrophages

Rahman

Muppala

et al. 2019

Preprint

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Thrombospondin-4 (TSP4) attracted a lot of attention recently as a result of new functions identified for this matricellular protein in cardiovascular, muscular, and nervous systems. We have previously reported that TSP4 promotes local vascular inflammation in mouse atherosclerosis model. A common variant of TSP4, P387-TSP4, was associated with increased cardiovascular disease risk in human population studies. In a mouse atherosclerosis model, TSP4 had profound effect on accumulation of macrophages in lesions, which prompted us to examine its effects on macrophages, more in detail in this report.We examined the effects of A387-TSP-4 and P387-TSP-4 on mouse macrophages in cell culture and in vivo in the model of LPS-induced peritonitis. In tissues and in cell culture, TSP4 expression was associated with inflammation: TSP4 expression was upregulated in peritoneal tissues in LPS-induced peritonitis, and pro-inflammatory signals, INFg, GM-CSF, and LPS, induced TSP4 expression in macrophages in vivo and in cell culture. Deficiency in TSP-4 in macrophages from Thbs4 -/mice reduced the expression of pro-inflammatory macrophage markers, suggesting that TSP-4 facilitates macrophage differentiation into pro-inflammatory phenotype. Expression of TSP4, especially more active P387-TSP4, was associated with higher cellular apoptosis. Cultured macrophages displayed increased adhesion to TSP4 and reduced migration in presence of TSP4, and these responses were further increased with P387 variant.We concluded that TSP4 expression in tissue macrophages and in cultured macrophages increases their accumulation in tissues during the acute inflammatory process and supports macrophage differentiation into a pro-inflammatory phenotype. In a model of acute inflammation, TSP4 supports pro-inflammatory macrophage apoptosis, a response that is closely related to their pro-inflammatory activity and release of pro-inflammatory signals. P387-TSP4 was found to be more active form of TSP4 in all examined functions.

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“…Although TSP4 ligands are not comprehensively investigated, recent work from our group and others identified several cell surface receptors that are used by TSP4 to exert its cellular effects. 14,17,27,28,33,34 We found that TSP4 regulates Mϕ migration and adhesion through α M and β 3 integrin subunits. 17 The migration of EC in presence of recombinant TSP4 relied on β 3 and α 2 integrin subunits (with α V β 3 not involved) and integrin α V β 5 , as well as on the GABA receptor α 2 δ-1, 14 a TSP4 receptor suggested by previous reports on the functions of TSP4 in nervous system.…”

Section: Introductionmentioning

confidence: 91%

“…1,2 Recent studies have demonstrated the importance of TSP4 in the cardiovascular system, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] cancer, 14,15,[18][19][20][21][22][23][24][25][26] and the nervous system. [27][28][29][30] Remarkably high levels of TSP4 have been found in failing and hypertrophied hearts, [11][12][13]16,31 atherosclerotic lesions, 17,31 and several cancers. 15,[18][19][20][21][22][23][24][25][26] These reports have placed considerable attention on this poorly studied TSP, but many of its functions and its regulation still remain unknown.…”

Section: Introductionmentioning

confidence: 99%

The P387 thrombospondin‐4 variant promotes accumulation of macrophages in atherosclerotic lesions

et al. 2020

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Thrombospondin‐4 (TSP4) is a pro‐angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease. Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Furthermore, the levels and distributions of the two TSP4 variants were assessed in human atherosclerotic arteries. In ApoE–/–/P387‐TSP4 knock‐in mice, lesions size measured by Oil Red O did not change, but the lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE–/–/P387‐TSP4 knock‐in mice compared to ApoE–/– mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387‐TSP4 knock‐in mice. TSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions without changing the size of lesions. P387 TSP4 is more active in supporting these pro‐inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.

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Thrombospondin-4 Promotes Neuronal Differentiation of NG2 Cells via the ERK/MAPK Pathway

Cited by 25 publications

References 35 publications

Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

Effects of thrombospondin-4 on pro-inflammatory phenotype differentiation and apoptosis in macrophages

Effect of Thrombospondin-4 on Pro-inflammatory Phenotype Differentiation and Apoptosis in Macrophages

The P387 thrombospondin‐4 variant promotes accumulation of macrophages in atherosclerotic lesions

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