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Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes.

ABSTRACT: Multipotent mesenchymal stem cells (MSCs) are promising candidates for regenerative cell-based therapy. The mechanisms underlying MSC differentiation and other functions relevant to therapeutic avenues remain however a matter of debate. Recent reports imply a critical role for intercellular contacts in MSC differentiation. We studied MSC differentiation to vascular smooth muscle cells (VSMCs) in a coculture model using human primary MSCs and VSMCs. We observed that under these conditions, MSCs did not undergo the expected differentiation process. Instead, they revealed an increased proliferation rate. The upregulated MSC proliferation was initiated by direct contacts of MSCs with VSMCs; indirect coculture of both cell types in transwells was ineffective. Intercellular contacts affected cell growth in a unidirectional fashion, since VSMC proliferation was not changed. We observed formation of so-called tunneling nanotubes (TNTs) between MSCs and VSMCs that revealed an intercellular exchange of a fluorescent cell tracker dye. Disruption of TNTs using cytochalasin D or latrunculin B abolished increased proliferation of MSCs initiated by contacts with VSMCs. Using specific fluorescent markers, we identified exchange of mitochondria via TNTs. By generation of VSMCs with mitochondrial dysfunction, we show that mitochondrial transfer from VSMCs to MSCs was required to regulate MSC proliferation in coculture. Our data suggest that MSC interaction with other cell types does not necessarily result in the differentiation process, but rather may initiate a proliferative response. They further point to complex machinery of intercellular communications at the place of vascular injury and to an unrecognized role of mitochondria in these processes.

SUBMITTER: Vallabhaneni KC

PROVIDER: S-EPMC3495124 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes.

Vallabhaneni Krishna C KC Haller Hermann H Dumler Inna I

Stem cells and development 20120713 17

Multipotent mesenchymal stem cells (MSCs) are promising candidates for regenerative cell-based therapy. The mechanisms underlying MSC differentiation and other functions relevant to therapeutic avenues remain however a matter of debate. Recent reports imply a critical role for intercellular contacts in MSC differentiation. We studied MSC differentiation to vascular smooth muscle cells (VSMCs) in a coculture model using human primary MSCs and VSMCs. We observed that under these conditions, MSCs d ...[more]

PMID: 22676452

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Project description:Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells.High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (? 2 ?m by 0.5 ?m), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery.These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease.

Dataset Information

Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes.

Publications

Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes.

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