Peripheral blood hematopoietic stem and progenitor cell frequency is unchanged in patients with alpha-1-antitrypsin deficiency

Abstract

Granulocyte-colony-stimulating factor (G-CSF)-induced hematopoietic stem and progenitor cell (HSPC) mobilization is associated with the release of neutrophil-derived proteases. Previously, we have shown that alpha-1-antitrypsin (AAT) inhibits these proteases in mice, resulting in inhibition of HSPC mobilization. Here, we studied the relationship between AAT and HSPC in steady state and cytokine-induced mobilization in humans. Patients with alpha-1-antitrypsin deficiency (AATD) have an 85-90 % decrease of AAT in the peripheral blood (PB). We hypothesized that this leads to increased proteolytic activity in the bone marrow and increased steady-state PB HSPC numbers. Using flow cytometry and semi-solid cell culture, we found no significant difference in PB HSPC in AATD patients (n = 18) as compared to controls (n = 22). Healthy stem cell donors (n = 43) were mobilized with G-CSF for 5 days and the number of CD45(+)/CD34(+) HSPC were determined in PB. We found that, during mobilization, PB AAT levels increased significantly, positively correlating with PB CD45(+)/CD34(+) cells (r = 0.31, p = 0.005). In conclusion, although serum AAT levels and HSPC mobilization in healthy stem cell donors are positively correlated, AAT is not an indispensable protease-inhibitor in the constitutive circulation of HSPC. These findings suggest a model in which both protease-dependent and -independent pathways contribute to HSPC mobilization.

Cytokine‐induced hematopoietic stem and progenitor cell mobilization: unraveling interactions between stem cells and their niche

“…57 with controls, patients deficient in AAT do not significantly differ with respect to the number of steady state peripheral blood HSPCs. 57 These findings suggest that both proteasedependent and -independent pathways play a role in HSPC mobilization. The extent to which each contributes to HSPC mobilization must be further elucidated.…”

“…In healthy human stem cell donors, AAT serum levels increase during G‐CSF–induced HSPC mobilization. This positively correlates with the increase in peripheral blood CD34 + cells . When compared with controls, patients deficient in AAT do not significantly differ with respect to the number of steady state peripheral blood HSPCs …”