Adult hematopoietic stem cells have a remarkable developmental plasticity — bone marrow cells can generate hepatocytes that repopulate the liver of mice with fumarylacetoacetate hydrolase deficiency (Fah^-/-) and correct this liver disease. It has been unclear if hepatocytes derived from bone marrow arise from changing potency through cell fusion or by direct differentiation of hematopoietic stem cells. Two papers in the March 31 Advanced Online Nature show that regenerating liver nodules in Fah^-/- transplant recipient mice are derived from donor hematopoietic cells that fused with host hepatocytes, and not from trans-differentiating hematopoietic stem cells or hepatic stem cells present in bone marrow.

Xin Wang and colleagues at the Oregon Health & Science University, Portland, US, transplanted Fah^-/- deficient mice with bone-marrow cells from Fanconi anemia group C gene (Fancc) homozygous mutant mice and Fah wild-type mice. They observed that the repopulating hepatocytes in the liver were heterozygous for alleles unique to the donor marrow, in contrast to the original homozygous donor cells. In addition, they found that hepatocytes transplanted from female donor mice into male recipients demonstrated 80 XXXY (diploid to diploid fusion) and 120 XXXXYY (diploid to tetraploid fusion) karyotypes, indicative of fusion between donor and host cells.

In the second paper, George Vassilopoulos and colleagues at the University of Washington, Seattle, US, confirmed that the hepatic nodules observed following bone marrow transplantation in Fah^-/- deficient mice contained more mutant than wild-type Fah alleles. These new hepatocytes expressed both donor and host genes, consistent with a polyploid genome formation by fusion of host and donor cells. In addition, they showed that the hematopoietic donor genome adopted a more hepatocyte-specific expression profile after cell fusion.

"These fused cells formed normal-appearing hepatocytes, proliferated, and ultimately corrected the underlying metabolic disorder. Although our data represent only one example of putative developmental plasticity in haematopoietic stem cells, other examples of this phenomenon could also be due to in vivo cell fusion," conclude Vassilopoulos et al.