The in vivo diffusion chamber (DC) method of marrow culture was used to determine if the injection of host mice with cyclophosphamide (CY) caused, through its cytotoxic action the release of a humoral factor(s) capable of initiating stem cell (${\rm CFU}\text{-}{\rm s}$) and granulocyte-macrophage progenitor cell (${\rm CFU}\text{-}{\rm c}$) proliferation. Host mice were injected with CY 1-4 days prior to 800 rad of60 Co WBI and implantation of DCs containing normal or 400 rad sublethally irradiated (SLI) marrow cells. The greatest proliferative response within${\rm CFU}\text{-}{\rm s}$ and${\rm CFU}\text{-}{\rm c}$ populations occurred in those mice injected with CY 3 days prior to implant. The marked${\rm CFU}\text{-}{\rm s}$ and${\rm CFU}\text{-}{\rm c}$ regeneration was initiated during the initial 24 hr of culture in both normal and SLI marrow cells. Thereafter growth rates were approximately the same. SLI marrow, however, showed a greater response to the humoral effects of CY injection than did normal marrow. These data provided evidence that CY induced the release of a diffusible factor(s) capable of accelerating regeneration of normal and sublethally irradiated${\rm CFU}\text{-}{\rm s}$ and${\rm CFU}\text{-}{\rm c}$, the magnitude of which was dependent upon the time elapsed between CY injected and implantation of DCs. The marked proliferative response of the SLI stem and progenitor cells to the humoral stimulation may be indicative of the heterogeneity of both${\rm CFU}\text{-}{\rm s}$ and${\rm CFU}\text{-}{\rm c}$ populations surviving sublethal radiation exposure. The target cells may have possessed a differential sensitivity to the factor(s) initiating cell proliferation.

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