PTP1B promotes focal complex maturation, lamellar persistence and directional migration

Malformed α-Synuclein (α-syn) aggregates in neurons are released into the extracellular space, activating microglia to induce chronic neuroinflammation that further enhances neuronal damage in α-synucleinopathies, such as Parkinson’s disease. The mechanisms by which α-syn aggregates activate and recruit microglia remain unclear, however. Here we show that α-syn aggregates act as chemoattractants to direct microglia toward damaged neurons. In addition, we describe a mechanism underlying this directional migration of microglia. Specifically, chemotaxis occurs when α-syn binds to integrin CD11b, leading to H2O2 production by NADPH oxidase. H2O2 directly attracts microglia via a process in which extracellularly generated H2O2 diffuses into the cytoplasm and tyrosine protein kinase Lyn, phosphorylates the F-actin–associated protein cortactin after sensing changes in the microglial intracellular concentration of H2O2. Finally, phosphorylated cortactin mediates actin cytoskeleton rearrangement and facilitates directional cell migration. These findings have significant implications, given that α-syn–mediated microglial migration reaches beyond Parkinson’s disease.

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Gp38k, a Protein Synthesized by Vascular Smooth Muscle Cells, Stimulates Directional Migration of Human Umbilical Vein Endothelial Cells

Experimental Cell Research ◽

10.1006/excr.1999.4511 ◽

1999 ◽

Vol 250 (1) ◽

pp. 168-173 ◽

Cited By ~ 167

Author(s):

Katherine M. Malinda ◽

Lourdes Ponce ◽

Hynda K. Kleinman ◽

Lisa M. Shackelton ◽

Albert J.T. Millis

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Umbilical Vein ◽

Muscle Cells ◽

Directional Migration ◽

Human Umbilical Vein ◽

Umbilical Vein Endothelial Cells

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Collagen I triggers directional migration, invasion and matrix remodeling of stroma cells in a 3D spheroid model of endometriosis

Scientific Reports ◽

10.1038/s41598-021-83645-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anna Stejskalová ◽

Victoria Fincke ◽

Melissa Nowak ◽

Yvonne Schmidt ◽

Katrin Borrmann ◽

...

Keyword(s):

Single Cells ◽

Fold Increase ◽

Experimental Models ◽

Collagen I ◽

Matrix Remodeling ◽

Clinical Tool ◽

Directional Migration ◽

Endometrial Cells ◽

Small Molecule Drugs ◽

Actomyosin Contraction

AbstractEndometriosis is a painful gynecological condition characterized by ectopic growth of endometrial cells. Little is known about its pathogenesis, which is partially due to a lack of suitable experimental models. Here, we use endometrial stromal (St-T1b), primary endometriotic stromal, epithelial endometriotic (12Z) and co-culture (1:1 St-T1b:12Z) spheroids to mimic the architecture of endometrium, and either collagen I or Matrigel to model ectopic locations. Stromal spheroids, but not single cells, assumed coordinated directional migration followed by matrix remodeling of collagen I on day 5 or 7, resembling ectopic lesions. While generally a higher area fold increase of spheroids occurred on collagen I compared to Matrigel, directional migration was not observed in co-culture or in 12Z cells. The fold increase in area on collagen I was significantly reduced by MMP inhibition in stromal but not 12Z cells. Inhibiting ROCK signalling responsible for actomyosin contraction increased the fold increase of area and metabolic activity compared to untreated controls on Matrigel. The number of protrusions emanating from 12Z spheroids on Matrigel was decreased by microRNA miR-200b and increased by miR-145. This study demonstrates that spheroid assay is a promising pre-clinical tool that can be used to evaluate small molecule drugs and microRNA-based therapeutics for endometriosis.

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