Physiologically significant effects of pH and oxygen tension on granulopoiesis

Objective. Granulocyte differentiation in the bone marrow (BM) takes place in regions with lower pH and O-2 tension (pO(2)) than those in the BM sinus es. This suggests that granulopoiesis will be enhanced at subvascular pH an d PO2. Materials and Methods. The effects of pH and pO(2) on granulocyte prolifera tion, differentiation, and granulocyte colony-stimulating factor receptor ( G-CSFR) expression were evaluated using mobilized peripheral blood CD34(+) cells directed down the granulocytic pathway with stem cell factor, interle ukin 3, interleukin 6, and G-CSF. Results. Cell expansion was enhanced at subvascular pH, with tw ice as many total cells and CD15(bright)/CD11b(+) late neutrophil precursors (myelocyt es, metamyelocytes, bands) produced at pH 7.07 to 7.21 as was produced at p H 7.38. Low pH accelerated the rate of differentiation concomitant with thi s increase in proliferation. Also, total, CD15(bright)/CD11b(-) (promyelocy tes, early myelocytes), and CD15(bright)/CD11b(+) cell expansion was enhanc ed at lower pO(2), with twice as many of each cell type produced at 5% O-2 as at 20% O-2. The effects of low pH and low pO(2) were additive, such that generation of total, CD15(bright)/CD11b(-), and CD15(bright)/CD11b(+) cell s was 3.5-, 2.4-, and 4.0-fold greater at pH 7.21 and 5% O-2 than at the st andard hematopoietic culture conditions of pH 7.38 and 20% OL. Low pH resul ted in faster upregulation of G-CSFR surface expression, whereas pO(2) had no effect on G-CSFR expression. Conclusion. These data provide compelling evidence that pH and pO(2) gradie nts within the Bh I play significant roles in regulating hematopoiesis, Mor e rapid granulocytic cell proliferation and differentiation at low pH may b e explained in part by more rapid G-CSFR expression, The ability to alter c ell development by manipulating pH and pO(2) has important implications for optimizing ex vivo production of neutrophil precursors. (C) 2000 Internati onal Society for Experimental Hematology. Published by Elsevier Science Inc .