Copyright © 2005, European Society of Cardiology
How much intimacy is compatible with survival for a cardiomyocyte?
aAMC Liver Center, Academic Medical Center, Meibergdreef 69-71, 1105 BK, Amsterdam, The Netherlands
bDepartment of Anatomy and Embryology, Maastricht University, Maastricht, The Netherlands
* Corresponding author. Email address: w.h.lamers{at}amc.uva.nl
Received 19 July 2005; accepted 25 July 2005
See also article by Driesen et al. (pages 37–46) in this issue.
Most forms of communication between cells occur at the plasma membrane via signal transduction molecules and only indirectly modify the cell's interior. It is easily conceivable that this safeguard is necessary for the cell to maintain the gradient in concentration of biochemical components between its interior and the environment. For similar defensive reasons, extracellular material that is taken up via endocytosis is shuttled to the lysosomes to terminate any inherent biological activity. Most cells, nevertheless, do permit a tightly regulated form of direct communication with other cells, even if they are phenotypically dissimilar, by allowing the formation of gap junctions. Gap junctions have a functional pore size of 
1.5 nm, which allows the passage of small (<1 kDa) molecules. Macromolecules, therefore, need "second messengers" generated at the cell membrane to affect composition or function of the cell's interior.
Almost at the other extreme of the spectrum, cells within a tissue can fuse to form a syncytium. Examples are the cells that form striated muscles, the placental syncytiotrophoblast, and osteoclasts. A characteristic feature of these examples of cell fusion is that the participating cells are phenotypically identical. This aspect appears to be important, as experimental fusion between cells originating from different tissues (creating so-called heterokaryons) often induces, in addition to genetic instability, reprogramming of the genome in one of the participating cell types [1]. This sequel has been useful to experimentally analyze the regulation of gene expression in these cells, but to what extent this type of cell–cell communication is functionally relevant in vivo is largely unexplored. It is well known, however, that viruses use the mechanism to penetrate cells without ending up in the endo-lysosomal compartment [2]. Furthermore, it appears that the putative capacity of bone marrow-derived cells (BMDCs) to contribute to the regeneration of adult tissues such as heart, liver, and brain has to be ascribed to cell fusion between BMDCs and cardiomyocytes, hepatocytes, or Purkinje cells, respectively, and is not due to transdifferentiation of these putative adult stem cells into terminally differentiated cells [3]. Although spontaneous, this type of cell fusion is apparently rare and of still unsubstantiated functional relevance.
One can wonder whether there are intermediate or transient forms of direct cell–cell communication that do allow the passage of macromolecules without sacrificing the cell's phenotypic identity. One example that could be cited are the so-called exosomes, endosome-derived vesicles that are produced by antigen-presenting cells (dendritic cells, B lymphocytes, but also enterocytes) to activate T cells [4-5]. Another, perhaps equally intriguing example is now reported by Driesen et al. [6] in this issue of Cardiovascular Research. In long-term co-cultures of adult rabbit cardiomyocytes and fibroblasts, they observed transient spontaneous heterocellular interactions between the fibroblasts and cardiomyocytes that, if lasting sufficiently long, resulted in the loss of cross-striation due to sarcomeric depletion (dedifferentiation) of the cardiomyocytes. The events started as early as 90 min after addition of the fibroblasts to the cardiomyocyte cultures with gap junction-mediated heterocellular communication followed by membrane fusion after 24 h and exchange of cytosolic contents after 48 h. The courtship between the fibroblasts and cardiomyocytes could be as short as 4.5 h and never resulted in the formation of a heterokaryon. Dedifferentiation in the form of cell flattening was only seen in cardiomyocytes that had been visibly pulled at by the fibroblasts. Using the EM, [6] observed membrane fusions between fibroblasts and cardiomyocytes that often measured 100–500 nm but could be as large as 6000 nm. Signs of apoptosis were not seen. When they investigated experimentally infarcted rabbit hearts, similar heterotypic cell contacts were seen at the border zone of the infarct areas. These data suggest that an aliquot of cytosol suffices to bring about one of the main effects attributed to cell fusion, reprogramming of the host nucleus. The authors propose that the observed partial heterocellular fusion opens up the therapeutic possibility of transferring cytoplasmic components into ailing cardiomyocytes without having to deal with the complications of producing heterokaryons. Although conceptually promising, the dominant signal conferred by the fibroblasts appears a dedifferentiating one, resembling the features seen in "hibernating" cardiomyocytes [7]. Furthermore, the authors ([6]) report that partial heterocellular fusion in vivo is confined to the twilight zone of an infarcted area, where the ischemic condition itself may suffice to induce the hibernating response.
The findings of Driesen and colleagues raise several questions. Thus, we can wonder whether the observed formation of heterotypic gap junctions is necessary for the subsequent membrane fusion to occur. If the (far more extensive) membrane fusion that accompanies skeletal muscle [8] and placental trophoblast [9] differentiation is based on a similar signal transduction mechanism, the answer is clearly yes. The observation that the heterotypic partial cell fusion in vivo was confined to the boundary of the infarcted area appears, on the other hand, to argue against this hypothesis, as gap junctions become smaller and sparser in this area [10]. Since [6] report that 3T3 cells can mediate the same effect as adult rabbit fibroblasts, co-culture of cardiomyocytes with connexin-deficient fibroblasts should be a straightforward approach to address this question.
Another finding that remains to be explained is the 24-h delay observed between the partial fusion of the membranes and the subsequent transfer of cytoplasm. At face value, this observation suggests that the contents of two cytosols are not freely diffusible and that transport of cytosol from one cell into the other requires adaptive structural remodeling. Such an interpretation may be compatible with the recent description of the cell's interior as a contractile, elastic network, of which the cytosol is the fluid phase [11] but clearly requires a better understanding if fibroblasts have to function as therapeutic vehicles.
The really intriguing question is how common transient, partial heterotypic cell fusions are in normal life. Driesen and colleagues did not quantify these interactions in their infarction model. Their observation that the partial cell fusions are most prevalent in the periphery of infarcted areas suggests that their development is facilitated by hypoxia or cell injury. However, the electron microscope does not seem to be a particularly suitable instrument to address this question. Instead, a modification of the Cre/lox recombination approach that showed that bone marrow-derived cells fuse with rather than transdifferentate into cardiomyocytes, hepatocytes, or neurons [12] appears promising. The modification that is required is that the experimental animals are chimeras containing cells that express Cre and cells that contain a loxP-flanked target gene. Such a model, which can be further refined by producing the chimera with male and female cells, will permanently mark mononuclear cells that have experienced a partial cell fusion. Depending on how common partial cell fusion is, we will know whether transient, intimate cell contacts are important or not to form and maintain a healthy body.
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