Transplanted blood progenitor cells can help repopulate a diseased liver, but they do this by fusing with existing liver cells, as opposed to reverting to a more pluripotent stem cell identity, according to two reports published online in Nature on March 30.

In recent years, extensive claims of stem cell plasticity have generated much excitement. The hypothesis posits that progenitor cells that already have a certain degree of specificity could be induced to "dedifferentiate"-to backtrack, as it were-to a wider phenotypic potential, or that they could even be reprogrammed (i.e., transdifferentiated) directly into progenitor status in a different lineage, without having to revert to an earlier, multipotent state. Some of the experimental support for this assumed plasticity came from findings that bone marrow stem cells, which are the progenitors of blood cell lineages, can be induced to produce other cell types, including neurons (Mezey et al., 2000) when transplantated to a new tissue environment.

Cautionary flags went up last year, when two papers showed that, in vitro, stem cells could fuse with differentiated cells, producing cells with two or even three sets of genetic material (see ARF related news story). In their paper describing fusion of embryonic neural stem cells with adult neurons, Austin Smith and colleagues remarked, "Our data raise a warning to the overzealous trend in stem cell research to conclude transdifferentiation or dedifferentiation of cells without careful examination of genotypes." (Ying et al., 2002) But these authors also noted that their findings were speculative and needed replication.

Support now comes from two independent in-vivo studies in a mouse model of a disorder involving the destruction of liver cells, which can be reversed by transplantation of haematopoietic stem cells. The renewed population of liver hepatocytes (which divide to repopulate the liver) has now been shown to be derived largely-perhaps even exclusively-from fused donor and recipient cells. Interestingly, the study by Wang et al. suggested that it is not the donor stem cell itself, but one of its differentiated progeny (possible macrophages or T or B cells) that actually fused with a local cell.

While the disorder in this model could be corrected, these results raise the sobering possibility that stem cells are not capable of true transdifferentiation across tissue types. "Although the frequency of spontaneous fusion resulting in [blood marrow-derived hepatocytes] is very low, it should nonetheless be noted that these cells can have therapeutic use when present in sufficient quantity. At present, this requires a strong selective growth advantage, but it is conceivable that induced cell fusion may achieve the efficiency necessary for the treatment of genetic diseases," write Wang and colleagues.—Hakon Heimer

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  1. There is much evidence that bone marrow stem cells acquire environmental cell characteristics by cell fusion (see ARF related news story; Spees et al., 2003). The fusion may be enough to reprogram gene expression patterns and result in changing cell fate decisions. Though when we consider that the spontaneous fusion rate is rather low, there are questions about whether this is the main mechanism for the multipotency of transplanted stem cells and whether this mechanism also occurs with endogenous stem cell differentiation. If this is a normal physiological response of stem cells, polyploidy found in AD neurons may be a result from neurogenesis through fusion. Nevertheless, it would be great if we could produce a variety of cell types from bone marrow stem cell, because it will allow us to develop autologous cell therapy. We should go after the use of adult bone marrow stem cell to treat neurodegenerative disease. Future studies would investigate the physiological function of the fused cell, and try to increase the efficacy of neural differentiation of bone marrow stem cells.

    References:

    . Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2397-402. PubMed.

References

News Citations

  1. Caution Flag for Adult Stem Cells: Fusion, Not Dedifferentiation?

Paper Citations

  1. . Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science. 2000 Dec 1;290(5497):1779-82. PubMed.
  2. . Changing potency by spontaneous fusion. Nature. 2002 Apr 4;416(6880):545-8. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. . Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature. 2003 Apr 24;422(6934):897-901. PubMed.
  2. . Transplanted bone marrow regenerates liver by cell fusion. Nature. 2003 Apr 24;422(6934):901-4. PubMed.