Mixed Chimerism of Bone Marrow Vessels (Endothelial Cells, Myofibroblasts) Following Allogeneic Transplantation for Chronic Myelogenous Leukemia

Abstract

Experimental findings support the hypothesis that within the functional network of the bone marrow (BM) microenvironment the endothelial cells (ECs) exert a pivotal role as gatekeepers by controlling the trafficking and homing of progenitor cells. However, little information is available concerning the origin of ECs after allogeneic bone marrow transplantation (BMT) in CML. To determine the extent of mixed chimerism (MCh) a simultaneous immunohistochemical and fluorescence in-situ hybridization (FISH) study was performed on BM biopsies derived from patients following sex-mismatched BMT with full unmanipulated BM. ECs were identified by their staining with CD34 and the myofibroblasts (MFs) of large vessels were labeled by an antibody against alpha-smooth muscle actin. For sex-typing and demonstration of the bcr/abl fusion product appropriate commercially available probes and detection systems were applied. Contrasting a total congruence of labeling in control samples five patients showed donor type ECs in the early posttransplant period in about 20%. In the remaining four patients the amount of donor type ECs increased slightly after the third month up to 30%. A total of 26 MFs could be identified lining large capillaries and arterioles that exclusively revealed a host origin. Following successful engraftment only very few of the persistent host-derived ECs also displayed the bcr/abl gene. In five patients, a conversion of MCh from donor to host type ECs was recognizable during the evolution of leukemic relapse. This finding was accompanied by a bcr/abl rearrangement of about 10% of these cells. In conclusion, following myelo-ablative therapy, a survival of a considerable number of ECs and MFs of the vessel walls has been found implying persistence of host-derived vascular structures of the BM stroma. However, in only a small proportion bcr/abl+ ECs and thus minimal residual disease was detectable. Evolution of leukemic relapse was characterized by conversion of MCh with almost total loss of donor type ECs and increase in number of bcr/abl+ ECs.

Persistence of recipient-type endothelium after allogeneic hematopoietic stem cell transplantation

“…Two earlier studies, which did not find donor-type endothelial cells in the stromal constituents of bone marrow up to 3 years after HSCT, 29,30 were contrasted by several reports showing endothelial cell chimerism in skin, gut, heart and bone marrow after gender-mismatched HSCT. [14][15][16][17][18]31,32 All these studies used XY in situ hybridization for the detection of donor-derived cells. Reported numbers of donor-type bone marrow-derived endothelial cells after HSCT varied from 2% in non-GVHD-affected skin and gastrointestinal tract up to 40% in the lung.…”

“…In support of this notion donor chimerism has been described in the endothelium of skin, gut, heart and bone marrow in patients after HSCT. [14][15][16] Furthermore, it was recently suggested that donorderived endothelial cells participate in endothelial repair during the effector phase of acute GVHD, 17 and donorderived endothelial cells were detected in 25% of sexmismatched skin biopsies following HSCT, especially in patients with acute GVHD, and at later time points. 18 Among others, ABH histo-blood group antigens expressed on endothelial cells represent a potential target for GVHD.…”

Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue

“…Therefore, a minimal dose-limiting effect may play a role when it comes to the contribution of transplanted, marrow-derived, true repopulating endothelial progenitors with the capacity to form HPP-ECs (CFU-ECs) [45]. Most of the bone marrow vasculature itself after lethal irradiation and whole bone marrow transplantation is host derived in humans [57] and in mice (H.G. Kopp, unpublished data), regardless of the degree of hematopoietic engraftment.…”

Differences in proportion and dynamics of recipient hematopoiesis following hematopoietic cell transplantation in CML and IMF

“…In combination with immunohistochemical analysis this assay allows the genotyping of single phenotyped cells. Assuming that in CMPD the source of relapse probably is the undifferentiated hematopoietic progenitor cell FISH analysis also is an important tool in monitoring hematopoietic engraftment in the BM after transplantation (26).…”