Signal through gp130 Activated by Soluble Interleukin (IL)‐6 Receptor (R) and IL‐6 or IL‐6R/IL‐6 Fusion Protein Enhances Ex Vivo Expansion of Human Peripheral Blood‐Derived Hematopoietic Progenitors

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Abstract
This study was designed to investigate the effects of a combination of soluble interleukin (sIL)‐6 receptor (R) and IL‐6 on the ex vivo expansion of human peripheral blood (PB)‐derived hematopoietic progenitor cells in a short‐term serum‐free liquid suspension culture system, using PB‐derived CD34+IL‐6R+/– cells as a target. In combination with stem cell factor (SCF), IL‐3, and sIL‐6R/IL‐6, the expansion efficiency (EE) for granulocyte/macrophage colony‐forming unit (CFU‐GM) reached a peak level on day 10 of incubation. On the other hand, the EE for erythroid burst (BFU‐E) and mixed colony‐forming unit (CFU‐Mix) reached a peak level on day 7 of incubation. Among the cytokine combinations tested, SCF + IL‐3 + sIL‐6R/IL‐6 + flt3 ligand (FL) most effectively expanded CFU‐GM and CFU‐Mix. The maximum EEs for CFU‐GM and CFU‐Mix were 208‐fold and 42‐fold, respectively. While the EE for BFU‐E was 70‐90‐fold in the presence of SCF + IL‐3 + sIL‐6R/IL‐6, FL significantly augmented the EE for CFU‐GM and CFU‐Mix. In contrast, thrombopoietin (TPO) significantly augmented the EE for CFU‐Mix. Interestingly, in combination with IL‐3 and SCF, newly generated IL‐6R/IL‐6 fusion protein (FP) expanded PB‐derived BFU‐E and CFU‐Mix twice more effectively than a combination of sIL‐6R and IL‐6. These results demonstrated that human PB‐derived committed progenitors were effectively expanded in vitro using sIL‐6R/IL‐6 or FP, in combination with IL‐3, SCF and/or FL or TPO, and that FP may transduce a stronger intracellular signal than a combination of sIL‐6R and IL‐6.

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