Sex-mismatched stem cell transplantation: a clinical model for solid-organ tissue regeneration
Martin Korbling Department of Stem Cell Transplantation and Cellular Therapy, Univ. of Texas M.D. Anderson Cancer Center, Unit 423, 1400 Holcombe Blvd., Houston, Texas 77030, USA
Abstract:
Sex-mismatched stem cell transplantation provides a unique opportunity to study the trafficking of donor- and peripheral blood (PB)-derived cells/stem cells into recipient non-hematopoietic solid-organ tissue. The Y-chromosome serves as a marker of donor-derived cells/stem cells identified in an XX female tissue.
The identification of recipient-derived Y-chromosome-positive cardiomyocytes in transplanted female cardiac tissue provided first evidence of PB as a potential vehicle of stem cell migration from recipient to donor tissue. Y-chromosome-positive solid-organ tissue cells have been identified as cardiac, liver, brain, GI, skin and other cells in female stem cell recipients. The frequency of donor-derived Y+ tissue cells has been reported in the range of 0.1 to 10% of non-hematopoietic tissue cells in various organ systems. Preclinical studies using more than one donor cell marker are either in favor, inconclusive, or do not support evidence for donor-derived stem cells transdifferentiating into solid-organ tissue cells.
On a clinical level we were able to show Y+ donor-derived keratinocytes, GI cells and liver cells in female stem cell transplant recipients. In a patient undergoing cord blood stem cell transplantation we identified Y+ CNS-specific cells in female CNS tissue. After male into female stem cell transplantation into a Philadelphia-positive CML patient we found endometrial tissue cells carrying the Y-chromosome and showing the abl-bcr translocation together in the same cells.
The mechanisms that explain how donor-derived genetic material is transferred to recipient solid-organ tissue cells are still being debated. Besides stem cell transdifferentiation which is believed to be a rare event, cell fusion is currently the preferred mechanism to explain the exchange of genetic material. Another hypothesis is the stimulation of the endogenous solid-organ tissue stem cell pool by paracrine secretion of transplanted cells or generation of donor-derived vascular tissue cells.
Most clinical trials using cells/stem cells for tissue repair, either published or being performed, rely on clinical outcome only, and are, therefore, difficult to interpret. The Y-chromosome provides an ideal marker to trace transplanted cells/stem cells to solid organ tissue in a female recipient.
