Wise Young
04-23-2003, 04:58 PM
Nature 422, 823 - 825 (2003); doi:10.1038/422823a
Stem cells: Fusion brings down barriers
ALEXANDER MEDVINSKY AND AUSTIN SMITH
Alexander Medvinsky and Austin Smith are at the Institute for Stem Cell Research, University of Edinburgh, King's Buildings, Edinburgh EH9 3JQ, UK.
e-mail: austin.smith@ed.ac.uk
It remains uncertain how tissue-specific stem cells could generate the mature cell types of another tissue. In one instance, where bone-marrow-derived stem cells repair damaged liver in mice, cell fusion is the answer.
The respective merits of embryonic versus adult stem cells for treating diseases have been widely discussed, in both the popular press and the scientific literature. In particular, reports that the developmental potential of adult stem cells might be greater than previously supposed have aroused strong interest and controversy. The papers by Wang and colleagues1 and Vassilopoulos and co-workers2 on pages 897 and 901 of this issue mark a further turn in the debate. These authors confirm that stem cells derived from adult bone marrow can repair damaged liver tissue in mice - but not by converting directly into liver cells, as might be expected if the stem cells could change their developmental 'destiny'. Instead, cell fusion with the host liver is responsible for bringing down the barriers between bone marrow and liver.
Many tissues and organs in adult mammals contain reserves of stem cells to ensure their long-term anatomical and functional maintenance. Stem cells are very few in number, but have both a high proliferation potential - allowing their lifelong renewal - and the capacity to generate fully mature, tissue-specific cell types. These strategic cell reserves are recruited in response to physiological demands or tissue damage.
Adult organs have generally been considered to be closed cell communities, reflecting their distinct developmental origins. Thus it was assumed, for instance, that stem cells from the brain are restricted to producing brain-specific mature cell types. Recently, however, the dogma of 'tissue fidelity' has been challenged. There have been reports that, following transplantation, cells derived from bone marrow can turn into liver, muscle, nerve and other specialized cell types. Conversely, it has been claimed that stem cells from the brain can produce blood or muscle. Such reports have given rise to the concept that stem cells from adult tissues are not constrained by their ancestry, and have the 'plasticity' to alter their destiny3.
But some investigators have been sceptical about these findings4. A key issue is the true identity of cells produced through 'tissue conversion'. To show that a certain cell type originated from a transplanted stem cell, the presence of both a marker gene from the donor and a tissue-specific protein must be demonstrated. But to show this unambiguously is technically demanding. And it is even more difficult to show that a particular cell, even if it appears to be specialized, actually functions in a tissue-specific way. In addition, 'converted' cells often occur singly, a fact that is difficult to reconcile with a stem-cell origin, which is expected to generate clusters of progeny.
These concerns appeared to be addressed in a study showing that mice with a fatal metabolic liver disease - a vital enzyme, fumarylacetoacetate hydrolase (Fah), is missing in these animals - can be 'rescued' by the transplantation of purified blood stem cells5. Histological examination revealed massive areas of healthy, donor-derived liver tissue. This observation was reproducible and the livers were demonstrably functional, as the animals survived. So blood can produce liver - but how? Do the blood stem cells directly generate liver cells (Fig. 1a)?
Figure 1 Possible mechanisms by which transplanted blood cells could transform into liver cells. Full legend
High resolution image and legend (49k)
It seems not. A well-known way by which cells can change identity is through cell fusion6. In hybrid cells produced by fusion, molecules from one fusion partner reprogramme gene expression in the genome of the other partner. Fusion can occur spontaneously in vitro - this was shown for the first time in the 1960s, and again more recently in reports7, 8 that also indicated that hybrid cells can function in vivo. Wang et al.1 and Vassilopoulos et al.2 now show unequivocally that the cells that build healthy liver tissue in Fah-deficient mice contain both donor and host genetic markers. Cells with such a genetic constitution can only have arisen by in vivo fusion. So, the donor cells effect functional rescue by delivering their genome, which includes the Fah gene, into pre-existing liver cells (Fig. 1b). In the resulting hybrids, liver-cell molecules dominate over blood-cell factors, so that liver gene expression is activated and blood gene expression is silenced.
The ancients recounted the myth of Prometheus, whose damaged liver was continuously regenerated. In this tale - and in liver regeneration in general - it is not stem cells that are required, but rather the proliferation of mature liver cells. In the new work1, 2, the contribution of the hybrid cells seems to depend on this regenerative context, and on the space created by degeneration of the diseased host liver. (This may explain why, in healthy liver, transplanted bone-marrow cells yield only single liver cells9.) The liver may also be a particularly favourable setting for hybrid cells, because normal liver cells often carry several copies of each chromosome; hybrids, too, generally have an additional set of chromosomes (Fig. 2).
Figure 2 Formation and reduction of hybrids. Full legend
High resolution image and legend (95k)
One important remaining question is exactly which cells fuse with the host liver; there is no evidence that it is the stem cells themselves. Instead, it seems more likely that differentiated progeny of the stem cells, such as blood cells known as macrophages, are responsible, because a contribution to the liver is seen only after the donor stem cells have populated the animals' blood system1, 2. It will be essential to identify the precise fusion partners in order to optimize any clinical applications. Another question is whether the Fah gene is already active in certain donor-derived blood cells, or whether it is activated after fusion. Furthermore, the extent to which gene expression throughout the genome is reprogrammed in hybrids - and whether this is prone to error, as is the case with cloning - will require meticulous investigation.
Another remarkable observation reported by Wang et al.1 is that some cells in the rescued liver contain only two copies (a pair) of each chromosome. How could fusion occur without an increase in chromosome number? The most probable explanation is that hybrid cells undergo a 'reduction division', in which an entire set of paired chromosomes is lost. Such reduction divisions will conceal fusion history (Fig. 2), introducing a further confounding factor to the investigation of tissue conversion.
The issue of stem-cell plasticity in its pure form - that is, whether a stem cell from one tissue can transform into a different tissue type - will remain open for some time. Last year's discovery of multipotent adult progenitor cells (MAPCs)10 added a further dimension. These cells can produce various mature cell types in isolation, and therefore without fusion. But how do MAPCs arise in the first place? They seem to develop over time in culture, possibly because they become liberated from tissue-restricted gene expression. Could it be that fusion between distinct tissue-specific cell types in the starting population creates hybrids that reprogramme to become MAPCs?
Our new understanding of how blood cells produce liver1, 2 should have an impact on research into the use of bone-marrow transplantation for treating certain genetic disorders: gene transfer through in vivo fusion now seems a distinct possibility. But the major applications of regenerative medicine seem likely to be delivered through embryonic and tissue-specific adult stem cells.
Stem cells: Fusion brings down barriers
ALEXANDER MEDVINSKY AND AUSTIN SMITH
Alexander Medvinsky and Austin Smith are at the Institute for Stem Cell Research, University of Edinburgh, King's Buildings, Edinburgh EH9 3JQ, UK.
e-mail: austin.smith@ed.ac.uk
It remains uncertain how tissue-specific stem cells could generate the mature cell types of another tissue. In one instance, where bone-marrow-derived stem cells repair damaged liver in mice, cell fusion is the answer.
The respective merits of embryonic versus adult stem cells for treating diseases have been widely discussed, in both the popular press and the scientific literature. In particular, reports that the developmental potential of adult stem cells might be greater than previously supposed have aroused strong interest and controversy. The papers by Wang and colleagues1 and Vassilopoulos and co-workers2 on pages 897 and 901 of this issue mark a further turn in the debate. These authors confirm that stem cells derived from adult bone marrow can repair damaged liver tissue in mice - but not by converting directly into liver cells, as might be expected if the stem cells could change their developmental 'destiny'. Instead, cell fusion with the host liver is responsible for bringing down the barriers between bone marrow and liver.
Many tissues and organs in adult mammals contain reserves of stem cells to ensure their long-term anatomical and functional maintenance. Stem cells are very few in number, but have both a high proliferation potential - allowing their lifelong renewal - and the capacity to generate fully mature, tissue-specific cell types. These strategic cell reserves are recruited in response to physiological demands or tissue damage.
Adult organs have generally been considered to be closed cell communities, reflecting their distinct developmental origins. Thus it was assumed, for instance, that stem cells from the brain are restricted to producing brain-specific mature cell types. Recently, however, the dogma of 'tissue fidelity' has been challenged. There have been reports that, following transplantation, cells derived from bone marrow can turn into liver, muscle, nerve and other specialized cell types. Conversely, it has been claimed that stem cells from the brain can produce blood or muscle. Such reports have given rise to the concept that stem cells from adult tissues are not constrained by their ancestry, and have the 'plasticity' to alter their destiny3.
But some investigators have been sceptical about these findings4. A key issue is the true identity of cells produced through 'tissue conversion'. To show that a certain cell type originated from a transplanted stem cell, the presence of both a marker gene from the donor and a tissue-specific protein must be demonstrated. But to show this unambiguously is technically demanding. And it is even more difficult to show that a particular cell, even if it appears to be specialized, actually functions in a tissue-specific way. In addition, 'converted' cells often occur singly, a fact that is difficult to reconcile with a stem-cell origin, which is expected to generate clusters of progeny.
These concerns appeared to be addressed in a study showing that mice with a fatal metabolic liver disease - a vital enzyme, fumarylacetoacetate hydrolase (Fah), is missing in these animals - can be 'rescued' by the transplantation of purified blood stem cells5. Histological examination revealed massive areas of healthy, donor-derived liver tissue. This observation was reproducible and the livers were demonstrably functional, as the animals survived. So blood can produce liver - but how? Do the blood stem cells directly generate liver cells (Fig. 1a)?
Figure 1 Possible mechanisms by which transplanted blood cells could transform into liver cells. Full legend
High resolution image and legend (49k)
It seems not. A well-known way by which cells can change identity is through cell fusion6. In hybrid cells produced by fusion, molecules from one fusion partner reprogramme gene expression in the genome of the other partner. Fusion can occur spontaneously in vitro - this was shown for the first time in the 1960s, and again more recently in reports7, 8 that also indicated that hybrid cells can function in vivo. Wang et al.1 and Vassilopoulos et al.2 now show unequivocally that the cells that build healthy liver tissue in Fah-deficient mice contain both donor and host genetic markers. Cells with such a genetic constitution can only have arisen by in vivo fusion. So, the donor cells effect functional rescue by delivering their genome, which includes the Fah gene, into pre-existing liver cells (Fig. 1b). In the resulting hybrids, liver-cell molecules dominate over blood-cell factors, so that liver gene expression is activated and blood gene expression is silenced.
The ancients recounted the myth of Prometheus, whose damaged liver was continuously regenerated. In this tale - and in liver regeneration in general - it is not stem cells that are required, but rather the proliferation of mature liver cells. In the new work1, 2, the contribution of the hybrid cells seems to depend on this regenerative context, and on the space created by degeneration of the diseased host liver. (This may explain why, in healthy liver, transplanted bone-marrow cells yield only single liver cells9.) The liver may also be a particularly favourable setting for hybrid cells, because normal liver cells often carry several copies of each chromosome; hybrids, too, generally have an additional set of chromosomes (Fig. 2).
Figure 2 Formation and reduction of hybrids. Full legend
High resolution image and legend (95k)
One important remaining question is exactly which cells fuse with the host liver; there is no evidence that it is the stem cells themselves. Instead, it seems more likely that differentiated progeny of the stem cells, such as blood cells known as macrophages, are responsible, because a contribution to the liver is seen only after the donor stem cells have populated the animals' blood system1, 2. It will be essential to identify the precise fusion partners in order to optimize any clinical applications. Another question is whether the Fah gene is already active in certain donor-derived blood cells, or whether it is activated after fusion. Furthermore, the extent to which gene expression throughout the genome is reprogrammed in hybrids - and whether this is prone to error, as is the case with cloning - will require meticulous investigation.
Another remarkable observation reported by Wang et al.1 is that some cells in the rescued liver contain only two copies (a pair) of each chromosome. How could fusion occur without an increase in chromosome number? The most probable explanation is that hybrid cells undergo a 'reduction division', in which an entire set of paired chromosomes is lost. Such reduction divisions will conceal fusion history (Fig. 2), introducing a further confounding factor to the investigation of tissue conversion.
The issue of stem-cell plasticity in its pure form - that is, whether a stem cell from one tissue can transform into a different tissue type - will remain open for some time. Last year's discovery of multipotent adult progenitor cells (MAPCs)10 added a further dimension. These cells can produce various mature cell types in isolation, and therefore without fusion. But how do MAPCs arise in the first place? They seem to develop over time in culture, possibly because they become liberated from tissue-restricted gene expression. Could it be that fusion between distinct tissue-specific cell types in the starting population creates hybrids that reprogramme to become MAPCs?
Our new understanding of how blood cells produce liver1, 2 should have an impact on research into the use of bone-marrow transplantation for treating certain genetic disorders: gene transfer through in vivo fusion now seems a distinct possibility. But the major applications of regenerative medicine seem likely to be delivered through embryonic and tissue-specific adult stem cells.