Recipes for adult stem cell plasticity: fusion cuisine or readymade?

Abstract

A large body of evidence supports the idea that certain adult stem cells, particularly those of bone marrow origin, can engraft at alternative locations, particularly when the recipient organ is damaged. Under strong and positive selection pressure these cells will clonally expand/differentiate, making an important contribution to tissue replacement. Similarly, bone marrow derived cells can be amplified in vitro and differentiated into many types of tissue. Despite seemingly irrefutable evidence for stem cell plasticity, a veritable chorus of detractors has emerged, some doubting its very existence, motivated perhaps by more than a little self interest. The issues that have led to this situation include the inability to reproduce certain quite startling observations, and extrapolation from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. Although these issues need resolving and, accepting that cell fusion does appear to allow reprogramming of haemopoietic cells in special circumstances, criticising this whole new field because some areas remain unclear is not good science.

Figure 1

Tracking bone marrow by sex mismatched bone marrow transplantation. Male to female transplantation is useful for detecting transdifferentiation by detection of the Y chromosome. However, cell fusion may be missed because not all chromosomes might be visible in the tissue section. Female to male transplantation is more suitable for detecting fusion events; marked bone marrow derived parenchymal cells with a Y chromosome have definitely been formed by fusion with host cells.

Figure 2

The early postnatal development of hepatocyte polyploidy is through the failure of cytokinesis, leading to the formation of binucleate cells (see text). This is quite distinct from the fusion of bone marrow cells with hepatocytes described in the Fah−/− mouse.

Figure 3

Patterns of bone marrow engraftment recorded in epithelial tissues. In the Fah−/− liver (left hand side), low levels of engraftment are followed by clonal expansion of the bone marrow cells that have fused with host hepatocytes and have been reprogrammed to produce Fah. In many renewing tissues (right hand side), persistent high levels of engraftment have been recorded, but no clonal expansion is seen, suggesting continued recruitment and loss, with no bone marrow derived cells establishing themselves as stem cells in their new location.