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Integrin ?6?1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

ABSTRACT: Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin ?6?1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that ?6?1 binding to LN1 was required for differentiation to ECs. ?6?1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signaling and mediated the EC lineage-specifying transcription factor Er71. In contrast, association of the ESC-expressed ?3?1, another highly expressed LN1 binding integrin, with CD151, prevented ?6?1-mediated differentiation. CD151 thus functioned as a bifurcation router to direct ESCs toward ECs when ?6?1 associated with CD151, or prevented transition to ECs when ?3?1 associated with CD151. These observations were recapitulated in mice in which ?6 integrin or CD151 knockdown reduced the expression of Er71-regulated angiogenesis genes and development of blood vessels. Thus, interaction of ?6?1 in ESCs with LN1 activates ?6?1/CD151 signaling which programs ESCs toward the EC lineage fate.

SUBMITTER: Toya SP

PROVIDER: S-EPMC4441581 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Integrin α6β1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

Toya Sophie P SP Wary Kishore K KK Mittal Manish M Li Fei F Toth Peter T PT Park Changwon C Rehman Jalees J Malik Asrar B AB

Stem cells (Dayton, Ohio) 20150601 6

Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin α6β1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that α6β1 binding to LN1 was required for differentiation to ECs. α6β1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signalin ...[more]

PMID: 25693840

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Project description:Unlabelled: We previously reported the delivery of endothelial progenitor cells (EPCs) embedded in hyaluronic acid-based (HA)-hydrogels protects renal function during acute kidney injury (AKI) and promotes angiogenesis. We attempted to further ameliorate renal dysfunction by coembedding EPCs with renal mesenchymal stem cells (MSCs), while examining their paracrine influence on cytokine/chemokine release and proinflammatory macrophages. A live/dead assay determined whether EPC-MSC coculturing improved viability during lipopolysaccharide (LPS) treatment, and HA-hydrogel-embedded delivery of cells to LPS-induced AKI mice was assessed for effects on mean arterial pressure (MAP), renal blood flow (RBF), circulating cytokines/chemokines, serum creatinine, proteinuria, and angiogenesis (femoral ligation). Cytokine/chemokine release from embedded stem cells was examined, including effects on macrophage polarization and release of proinflammatory molecules. EPC-MSC coculturing improved stem cell viability during LPS exposure, an effect augmented by MSC hypoxic preconditioning. The delivery of coembedded EPCs with hypoxic preconditioned MSCs to AKI mice demonstrated additive improvement (compared with EPC delivery alone) in medullary RBF and proteinuria, with comparable effects on serum creatinine, MAP, and angiogenesis. Exposure of proinflammatory M1 macrophages to EPC-MSC conditioned medium changed their polarization to anti-inflammatory M2. Incubation of coembedded EPCs-MSCs with macrophages altered their release of cytokines/chemokines, including enhanced release of anti-inflammatory interleukin (IL)-4 and IL-10. EPC-MSC delivery to endotoxemic mice elevated the levels of circulating M2 macrophages and reduced the circulating cytokines/chemokines. In conclusion, coembedding EPCs-MSCs improved their resistance to stress, impelled macrophage polarization from M1 to M2 while altering their cytokine/chemokines release, reduced circulating cytokines/chemokines, and improved renal and vascular function when MSCs were hypoxically preconditioned.SignificanceThis report provides insight into a new therapeutic approach for treatment of sepsis and provides a new and improved strategy using hydrogels for the delivery of stem cells to treat sepsis and, potentially, other injuries and/or diseases. The delivery of two different stem cell lines (endothelial progenitor cells and mesenchymal stem cells; delivered alone and together) embedded in a protective bioengineered scaffolding (hydrogel) offers many therapeutic benefits for the treatment of sepsis. This study shows how hydrogel-delivered stem cells elicit their effects and how hydrogel embedding enhances the therapeutic efficacy of delivered stem cells. Hydrogel-delivered stem cells influence the components of the overactive immune system during sepsis and work to counterbalance the release of many proinflammatory and prodamage substances from immune cells, thereby improving the associated vascular and kidney damage.

Dataset Information

Integrin ?6?1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

Publications

Integrin α6β1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

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