Unveiling the Mechanisms of Cell-Cell Fusion

Chen, Elizabeth H.; Olson, Eric N.

doi:10.1126/science.1104799

Cited by 335 publications

(281 citation statements)

References 80 publications

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“…Numerous studies suggest cell fusion may be responsible for the plasticity and tissue regeneration potential of adult stem cells [2,7,8,34,39,46]. Cell or nuclear fusion may account for the coexpression of donor and recipient cell markers [2,34,40,42].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell and Nucleus Pulposus Cell Coculture Modulates Cell Profile

Niu

Yuan

Lin

et al. 2008

Clin Orthop Relat Res

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Spontaneous cell fusion can occur in cocultured stem cells. We examined whether telomerase activity change and cell fusion occurred in mesenchymal stem cell (MSC) and nucleus pulposus cell (NPC) coculture. MSCs and NPCs were labeled with PKH26 and PKH67 dyes and cocultured at a 50:50 ratio. An equal number of MSCs or NPCs were used as the control. After 14 days, cells were evaluated by cell growth, telomerase activity, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry, and histologic observation. Cell fusion was confirmed by microscopic observation and fluorescence-activated cell sorter (FACS) analysis. The results suggested cell growth rate and telomerase activity were higher in cocultured cells than in NPCs cultured alone. The mRNA expression levels of the Type II collagen and aggrecan were elevated in cocultured cells. Immunohistochemical analysis revealed positive staining for Type II collagen and keratan sulfate in NPCs cultured alone and in a proportion of cocultured cells. Histologic observation revealed binucleated cocultured cells expressed both PKH dyes in the same location and slide focus. The FACS analysis revealed 42% of cocultured cells were doublestained. Cocultured cells partially maintained the NPC phenotype. The partially maintained phenotype of the NPCs may be attributable to spontaneous cell fusion in association with increased telomerase activity.

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Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell and Nucleus Pulposus Cell Coculture Modulates Cell Profile

Niu

Yuan

Lin

et al. 2008

Clin Orthop Relat Res

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“…Moreover, in addition to turning on proinsulin expression, the diabetic state also induces TNF-␣ expression in BMDC, consistent with diabetes causing reprogramming of bone marrow cells to express ''inappropriate'' genes. We speculate that among these are fusion-promoting genes, and dysregulated gene expression in BMDC and/or hepatocytes predisposes them to fuse with each other (24). Thus, diabetes-induced abnormal gene expression is important not only from the standpoint of the pathophysiology of diabetes (25)(26)(27) but also from the standpoint of the fundamental biology of cell fusion and its regulation (24).…”

Section: Discussionmentioning

confidence: 99%

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Fujimiya

Kojima

Ichinose³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We previously reported that diabetes in mice is associated with the appearance of proinsulin-producing (Proins-P) cells in the liver. It was unclear, however, whether these Proins-P bone marrowderived cells (BMDC) merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-␣, suggesting that diabetes reprograms gene expression in BMDC, turning on ''inappropriate'' genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute Ϸ2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion.cell fusion ͉ diabetes mellitus ͉ diabetic complications ͉ liver R ecent reports from different laboratories document that bone marrow-derived cells (BMDC) can fuse with hepatocytes in vivo, and such fusion events can contribute to liver regeneration (1-4). However, with the exception of unique genetic models, e.g., fumarylacetoacetate hydrolase (Fah)-deficient mice (1, 2), in which wild-type BMDC confer a marked growth advantage, BMDC-hepatocyte fusion appears to be extremely rare. In a review article, Thorgeirsson and Grisham (5) estimated that transplanted BMDC generate hepatocyte-like cells in the liver at a frequency of Յ10 O4 . In fact, the yield of presumed BMDC-hepatocyte fusion cells ranges from 0 to Ͻ0.05% in Ͼ80% of reports published before August 2005 (5). Apart from the rarity of the event, there is little information on whether BMDC-hepatocyte cell fusion is regulated by physiological body functions, and whether it is affected by pathological conditions other than the extreme example of Fah-deficient mice that received bone marrow transplantation (BMT) from Fahexpressing mice.Our laboratory recently reported the appearance of proinsulin-producing (Proins-P) cells in the bone marrow of diabetic rats and mice (6). The Proins-P BMDC migrate out of the bone marrow and populate different organs and tissues, including liver and fat. Because the phenomenon occurs in both type 1 and type 2 models, and can be duplicated by glucose injections in mice, hyperglycemia appears to trigger its occurrence. This interpretation is supported by the observation that Ϸ50% of unfractionated BMDC start transcribing insulin within days of incubation in high-glucose medium (7).Diabetes mellitus is a prevalent disease that affects Ϸ7% of the U.S. population and a rapidly growing proportion o...

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“…13 In spite of the diversity of cell types that undergo fusion, the underlying cellular processes, including cell-cell adhesion, alignment and membrane mixing, are similar irrespective of the cell type. 14 In this regard, tetraspanins and ADAMs (A Disintegrin And Metalloprotease domain) proteins have been implicated in cell fusion processes. In particular, tetraspanin CD9 and CD81 have been implicated in muscle cell fusion, mononuclear phagocytes and linked to the virus-induced syncitium formation.…”

Section: Introductionmentioning

confidence: 99%

Cell fusion promotes chemoresistance in metastatic colon carcinoma

et al. 2012

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Chemoresistance is an important concern in the treatment of metastatic colon cancer. It may emerge through selection of clones that are inherently resistant from the outset or through mechanisms acquired during treatment. Cell fusion represents an efficient means of rapid phenotypic evolution that make cells with new properties at a rate exceeding that achievable by random mutagenesis. Here, we first identified a number of proteins involved in cell fusion using a shotgun proteomics approach, then we investigated the role of these proteins namely tetraspanin CD81/CD9, ADAM10, GTP-binding protein a13, radixin, myosin regulatory light chain and RhoA in the regulation of colon cancer cell fusion. We also found a previously unrecognized role of ADAM10, Ga13 and RhoA in promoting cell fusion. Finally, we show that the occurrence of cell fusion in a metastatic model of colon carcinoma causes the appearance of cells resistant to both 5-fluorouracil and oxaliplatin. These findings highlight the importance of cell fusion in cancer progression and raise significant implications for overcoming chemoresistance in metastatic colon cancer.

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Unveiling the Mechanisms of Cell-Cell Fusion

Cited by 335 publications

References 80 publications

Mesenchymal Stem Cell and Nucleus Pulposus Cell Coculture Modulates Cell Profile

Mesenchymal Stem Cell and Nucleus Pulposus Cell Coculture Modulates Cell Profile

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

Cell fusion promotes chemoresistance in metastatic colon carcinoma

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