Accelerated recovery of peripheral blood cell counts in mice transplanted with in vitro cytokine-expanded hematopoietic progenitors.
Interleukin 1 (IL-1) and interleukin 3 (IL-3) act synergistically in stimulating the growth of primitive hematopoietic progenitors. Murine bone marrow (BM) harvested 24 h after 5-fluorouracil (5-FU) administration (d1 5-FU BM) was stimulated with IL-1 and IL-3 to expand its progenitor pool during 7 days of suspension culture (delta-culture), and this in vitro expanded BM was compared to fresh d1 5-FU BM in its ability to reconstitute lethally irradiated or high-dose 5-FU-treated hosts. Transplantation with expanded delta-culture BM was found to dramatically shorten the period of cytopenia following lethal irradiation as compared to animals receiving d1 5-FU BM. Recipients of delta-cultured BM demonstrated accelerated recoveries of peripheral blood leukocytes, neutrophils, platelets, and erythrocytes. Furthermore, expansion of BM in vitro reduced the number of BM cells required for engraftment following lethal irradiation. Treatment of lethally irradiated mice with IL-1 and granulocyte colony-stimulating factor (G-CSF) following transplantation with delta-cultured BM or d1 5-FU BM further improved the recovery of neutrophils in these hosts. In conjunction with G-CSF post-transplantation cytokine therapy, high-dose 5-FU-treated mice transplanted with delta-cultured BM also demonstrated improved recovery kinetics of neutrophils and erythrocytes. Five and 10 weeks after BM transplantation, a decrease in the proliferative capacity of the earliest hematopoietic progenitors, detected in assays of primary and delta-culture generated-secondary high proliferative potential colony-forming cells (HPP-CFC), was found in all transplanted mice following a chemotherapy challenge with 5-FU. However, this impairment in the early progenitor/stem cell pool was not noticeably worsened by the expansion of BM in delta-cultures. The decrease in host hematopoietic proliferative potential associated with transplantation of limiting numbers of BM cells was not reversed over the 10 weeks of this study. The expansion of BM progenitor cells without loss of long-term proliferative potential may be of clinical importance in the fields of BM transplantation and gene therapy.
Muench
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MO
James Ewing Laboratory of Developmental Hematopoiesis, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Moore
M A
MA
D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation / Q000502:physiology; D003131:Combined Modality Therapy; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects; D006410:Hematopoiesis / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009504:Neutrophils / Q000187:drug effects; D010198:Pancytopenia / Q000139:chemically induced / Q000628:therapy*; D014916:Whole-Body Irradiation
D007375:Interleukin-1; D007377:Interleukin-3; D005472:Fluorouracil