Abstract
Following transplantation of hematopoietic lineage cells, genetic markers unique to the transplanted cells have been detected in non-hematopoietic recipient cells of human liver, vascular endothelium, intestinal epithelium and brain. The underlying mechanisms by which this occurs are unclear. Evidence from mice suggests it is due in part to fusion between cells of hematopoietic and non-hematopoietic origins; however, direct evidence for this in humans is scant. Here, by quantitative and statistical analysis of X- and Y-chromosome numbers in epithelial and non-epithelial intestinal cells from gender-mismatched hematopoietic cell transplant patients, we provide evidence that transplanted cells of the hematopoietic lineage incorporate into human intestinal epithelium through cell fusion. This is the first definitive identification of cell fusion between hematopoietic cells and any epithelial cell type in humans, and provides the basis for further understanding the physiological and potential pathological consequences of cell fusion in humans.
Highlights
In patients who received hematopoietic cell transplantation, genetic markers specific to transplanted hematopoietic lineage cells have been found in fully differentiated cells of multiple nonhematopoietic tissues, including liver, brain, vascular endothelia, intestinal epithelia and cancerous tissue [1,2,3,4,5]
By quantitative and statistical analysis of X- and Y-chromosome numbers in individual epithelial and non-epithelial nuclei of gender-mismatched hematopoietic cell transplant patients, we demonstrate that cell fusion is one mechanism by which hematopoietic lineage cells incorporate into the human gastrointestinal epithelium
In this study we demonstrate that cell fusion is one mechanism by which genetic markers of hematopoietic cells are incorporated into human intestinal epithelium
Summary
In patients who received hematopoietic cell transplantation, genetic markers specific to transplanted hematopoietic lineage cells have been found in fully differentiated cells of multiple nonhematopoietic tissues, including liver, brain, vascular endothelia, intestinal epithelia and cancerous tissue [1,2,3,4,5]. While there have been repeated demonstrations in humans that genetic markers specific to hematopoietic cells can be found in non-hematopoietic cell types, there have been very few attempts to conduct quantitative analysis at the single-cell level to definitively identify whether this occurs via hematopoietic transdifferentiation or cell fusion. Distinguishing between these mechanisms is necessary in order to guide subsequent investigation towards the plasticity of hematopoietic progenitor cells or the phenotypic outcomes of fusion between different cell types. One obvious feature that distinguishes cells derived from fusion relative to transdifferentiation as a mechanism for the origin of non-hematopoietic cells carrying hematopoietic-specific genetic markers is that cell fusion results in a direct and immediate increase in cellular chromosomes content, while transdifferentiation does not
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