Marrow repopulating cells in mobilized PBPC can be serially transplanted for up to five generations or be remobilized in PBPC reconstituted mice

Abstract

Summary:We have evaluated the durability of engraftment and the potential of remobilization in mice reconstituted with mobilized peripheral blood progenitor cells (PBPC). Female mice which had been reconstituted with cytokine-mobilized PBPC from male donors were serially transplanted into second, third, fourth and fifth lethally irradiated female recipients at intervals of 6-10 months. Male-derived hematopoiesis was determined in recipient mice at each serial transplantation. Male-positive CFCs were detected after 5 passages for 45 months, but declined from Ͼ95% at passage 1 to 74% at passage 2, 33% at passage 4, and 28% at passage 5. Long-term survival also declined from 97% at passage 2 to 53% at passage 4, and 27% at passage 5. The results demonstrated that mobilized PBPC were able to provide engraftment for more than 45 months, but the engraftment provided by mobilized PBPC decreased at each serial passage. In addition, mice reconstituted with mobilized PBPC (at 1 year post transplantation) were treated with the same cytokines as in the primary mobilization (remobilization). The remobilized PBPC were harvested and transplanted into lethally irradiated secondary recipients. Male-derived CFCs were evaluated at 20 months post transplantation. Mice transplanted with PBPC remobilized with rhG-CSF or rhG-CSF plus rrSCF-PEG showed 70% and 89% male-positive CFCs respectively, demonstrating that mice reconstituted with mobilized PBPC could be remobilized and that the remobilized PBPC were also capable of providing longterm hematopoietic reconstitution. Our studies demonstrated that mobilized PBPC have extensive proliferative or self-renewal capacity to provide durable engraftment and that marrow repopulating cells in PBPC reconstituted mice can be remobilized, suggesting that patients who relapse after PBPC transplantation may be remobilized for a second transplantation to support additional chemotherapy.

The human–sheep chimeras as a model for human stem cell mobilization and evaluation of hematopoietic grafts' potential

“…The large amount of accessory cells present in peripheral blood could potentially also allow for immunomodulatory approaches to enhance graft versus tumor response following transplantation [1,2]. While several authors have reported differences in the phenotype, cell cycle status, and amount of stem cells present in PBSC versus BMHSC [10][11][12][13][14][15][16][17][18][19][20][21], other research groups have devoted their attention to the mechanisms by which HSC are mobilized [22][23][24][25][26][27]. Still, a further understanding of the mechanisms of mobilization and the quality and biological characteristics of stem cell subsets in peripheral blood with respect to both the level and durability of engraftment they provide would likely contribute to the development of safer, more predictable and efficacious mobilization protocols with higher safety.…”