Long-lasting decrease of marrow and circulating long-term culture initiating cells after allogeneic bone marrow transplant

Abstract

Summary:We investigated bone marrow (BM) and circulating (PB) hematopoietic progenitor cells in 37 normal donors and in 25 patients 1 to 8 years after successful allogeneic bone marrow transplant. At the time of testing, transplanted patients had normal blood counts and bone marrow cellularity. By flow cytometry, BM CD34 + cells were found to be three-to four-fold decreased in transplanted patients compared to normal donors, while the number of PB CD34+ cells was the same as in normal donors. Using a methylcellulose colony assay, primary BM colony-forming cells (CFU-GM) were decreased 2.1-fold, whereas PB CFU-GM were only marginally decreased. In a long-term culture initiating cell (LTC-IC) assay, an eight-fold decrease of early progenitor cells was observed in the marrow of transplanted patients compared to normal donors, and a five-fold decrease was documented in peripheral blood. We found that the BM LTC-IC cell number correlated with concurrently determined BM CD34 + cells and committed progenitor cell number (measured as CFU-GM) and with PB LTC-IC number, but not with PB CFU-GM and CD34+ cells. We conclude that marrow and circulating early stem cell compartments, as measured by the LTC-IC assay, are greatly and permanently depressed following bone marrow transplant. The correlation between BM and PB LTC-IC indicates that the enumeration of circulating LTC-IC can be used as a measure of the stem cell compartment in the bone marrow after transplant. It seems that the deficiency of the most immature progenitor cells persists forever after successful bone marrow transplant; this means that a complete hematopoietic reconstitution can be sustained by a reduced stem cell pool. Keywords: CD34 + ; LTC-IC; BMT Long-term survivors after allogeneic bone marrow transplantation (BMT) have normal marrow cellularity and normal peripheral blood cell counts. Due to intrinsic experimental problems with measurement of the human stem cell

Replicative stress after allogeneic bone marrow transplantation: changes in cycling of CD34+CD90+ and CD34+CD90− hematopoietic progenitors

“…The accentuated decline in the CD90 ϩ subset reported here suggests that this deficit is most pronounced in primitive progenitors, and it anticipates the finding that post-BMT reductions in long-term-culture-initiating cells are more profound, and prolonged, than reductions in LCPs. 4,5 Our results imply that early hematopoietic reconstitution after BMT is associated with a compensatory increase in mitotic rate in a population of CD34 ϩ CD90 ϩ progenitors. The accelerated proliferation of these cells is the most likely cause of the striking telomere shortening observed in leukocytes of BMT recipients, 6-8 though direct correlation must be sought in future studies.…”

“…The weight of existing evidence suggests that absolute numbers of both subsets are diminished for prolonged periods after transplantation. [1][2][3][4][5] Selleri et al 5 examined the bone marrow of BMT donors and recipients and found 3-to 4-fold fewer CD34 ϩ cells in the marrow of recipients as late as 8 years after BMT. The accentuated decline in the CD90 ϩ subset reported here suggests that this deficit is most pronounced in primitive progenitors, and it anticipates the finding that post-BMT reductions in long-term-culture-initiating cells are more profound, and prolonged, than reductions in LCPs.…”

“…However, recipients have profound deficits in hematopoietic progenitors (determined by functional assays and absolute CD34 ϩ cell enumeration) persisting for more than 10 years after BMT. [1][2][3][4][5] The demonstration of accelerated telomere shortening in leukocytes of BMT recipients, [6][7][8] reflecting an increase in the mitotic rate of bone marrow progenitors and/or stem cells, suggests that hematopoietic reconstitution imposes a "replicative stress" upon the graft. The distribution of this stress within the hematopoietic hierarchy is unknown and is of considerable importance.…”

Multi-color immune-phenotyping of CD34 subsets reveals unexpected differences between various stem cell sources

“…19,29 Both observations, the loss of earlier and the gain of more committed CD34 subtypes are in line with other reports. Selleri et al 37 found an eightfold decrease of long-term culture initiating cells in the BM of patients as compared with donors, and Thornley et al 30 described a higher telomere loss in the BM of patients with full donor chimerism. Woolthuis et al 38 reported a loss of quiescence and impaired function of CD34 + /CD38 low cells 1 year after autologous stem cell reinfusion.…”

Quantitative modeling of chronic myeloid leukemia: insights from radiobiology

“…There is some evidence for a "dead-band" in the control of HSC numbers, [90][91][92][93] as described in Radivoyevitch et al 87 ; here "dead" refers to the putative nonresponsive character of the HSC feedback control system when HSC numbers are more than sufficient to maintain a hematopoietic system. This postulate is an example of the systems biology concept of bounded autonomy.…”