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Tunneling-nanotube direction determination in neurons and astrocytes.

ABSTRACT: A tunneling nanotube (TNT) is a newly discovered structure involved in cell-cell communication and is found in various types of cells. Here we identify S100A4 as an extracellular molecule and describe its role in attracting the growth direction of TNTs. Together with its putative receptor, receptor for advanced glycation end product, we demonstrate their involvement in TNT direction guidance. Our results further suggest a mechanism for direction guidance of TNTs. In TNT-initiating cells, p53 activates caspase-3, which leads to S100A4 cleavage and its subsequent decrease in cellular concentration. The decrease in cellular S100A4 induces the formation of a gradient of S100A4, from a low concentration in initiating cells toward a high concentration in target cells. This concentration gradient of S100A4 induces direction guidance for TNTs.

SUBMITTER: Sun X

PROVIDER: S-EPMC3542613 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Tunneling-nanotube direction determination in neurons and astrocytes.

Sun X X Wang Y Y Zhang J J Tu J J Wang X-J XJ Su X-D XD Wang L L Zhang Y Y

Cell death & disease 20121206

A tunneling nanotube (TNT) is a newly discovered structure involved in cell-cell communication and is found in various types of cells. Here we identify S100A4 as an extracellular molecule and describe its role in attracting the growth direction of TNTs. Together with its putative receptor, receptor for advanced glycation end product, we demonstrate their involvement in TNT direction guidance. Our results further suggest a mechanism for direction guidance of TNTs. In TNT-initiating cells, p53 act ...[more]

PMID: 23222508

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Project description:Tunneling nanotubes (TNTs) are cellular extensions enabling cytosol-to-cytosol intercellular interaction between numerous cell types including macrophages. Previous studies of hematopoietic stem and progenitor cell (HSPC) transplantation for the lysosomal storage disorder cystinosis have shown that HSPC-derived macrophages form TNTs to deliver cystinosin-bearing lysosomes to cystinotic cells, leading to tissue preservation. Here, we explored if macrophage polarization to either proinflammatory M1-like M(LPS/IFN?) or anti-inflammatory M2-like M(IL-4/IL-10) affected TNT-like protrusion formation, intercellular transport and, ultimately, the efficacy of cystinosis prevention. We designed new automated image processing algorithms used to demonstrate that LPS/IFN? polarization decreased bone marrow-derived macrophages (BMDMs) formation of protrusions, some of which displayed characteristics of TNTs, including cytoskeletal structure, 3D morphology and size. In contrast, co-culture of macrophages with cystinotic fibroblasts yielded more frequent and larger protrusions, as well as increased lysosomal and mitochondrial intercellular trafficking to the diseased fibroblasts. Unexpectedly, we observed normal protrusion formation and therapeutic efficacy following disruption of anti-inflammatory IL-4/IL-10 polarization in vivo by transplantation of HSPCs isolated from the Rac2-/- mouse model. Altogether, we developed unbiased image quantification systems that probe mechanistic aspects of TNT formation and function in vitro, while HSPC transplantation into cystinotic mice provides a complex in vivo disease model. While the differences between polarization cell culture and mouse models exemplify the oversimplicity of in vitro cytokine treatment, they simultaneously demonstrate the utility of our co-culture model which recapitulates the in vivo phenomenon of diseased cystinotic cells stimulating thicker TNT formation and intercellular trafficking from macrophages. Ultimately, we can use both approaches to expand the utility of TNT-like protrusions as a delivery system for regenerative medicine.

Dataset Information

Tunneling-nanotube direction determination in neurons and astrocytes.

Publications

Tunneling-nanotube direction determination in neurons and astrocytes.

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