Extracellular annexin-A1 promotes myeloid/granulocytic differentiation of hematopoietic stem/progenitor cells via the Ca2+/MAPK signalling transduction pathway

Author(s)

Barbosa, V, Christiano M. ; Fock, Ricardo Ambrosio ^[1] ; Hastreiter, Araceli Aparecida ^[1] ; Reutelingsperger, Cris ^{[2, 3]} ; Perretti, Mauro ^[4] ; Paredes-Gamero, Edgar J. ^{[5, 6]} ; Farsky, Sandra H. P. ^[1]

Affiliation

^[1] Barbosa, Christiano M., V, Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[2] Maastricht Univ, CARIM Sch Cardiovasc Dis, NL-6200 MD Maastricht - Netherlands

^[3] Maastricht Univ, Dept Biochem, NL-6200 MD Maastricht - Netherlands

^[4] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London - England

^[5] Univ Fed Sao Paulo, Dept Biochem, Sao Paulo - Brazil

^[6] Fed Univ Mato Grosso do Sul UFMS, Sch Pharmaceut Sci Food & Nutr FACFAN, BR-79070900 Campo Grande, MS - Brazil

• Document type: Journal article
• Source: CELL DEATH DISCOVERY; v. 5, SEP 23 2019.
• Web of Science Citations: 0

Abstract

Annexin A1 (AnxA1) modulates neutrophil life span and bone marrow/blood cell trafficking thorough activation of formyl-peptide receptors (FPRs). Here, we investigated the effect of exogenous AnxA1 on haematopoiesis in the mouse. Treatment of C57BL/6 mice with recombinant AnxA1 (rAnxA1) reduced the granulocyte-macrophage progenitor (GMP) population in the bone marrow, enhanced the number of mature granulocytes Gr-1(+)Mac-1(+) in the bone marrow as well as peripheral granulocytic neutrophils and increased expression of mitotic cyclin B1 on hematopoietic stem cells (HSCs)/progenitor cells (Lin(-)Sca-1(+)c-Kit(+): LSK). These effects were abolished by simultaneous treatment with Boc-2, an FPR pan-antagonist. In in vitro studies, rAnxA1 reduced both HSC (LSKCD90(low)FLK-2(-)) and GMP populations while enhancing mature cells (Gr1(+)Mac1(+)). Moreover, rAnxA1 induced LSK cell proliferation (Ki67(+)), increasing the percentage of cells in the S/G2/M cell cycle phases and reducing Notch-1 expression. Simultaneous treatment with WRW4, a selective FPR2 antagonist, reversed the in vitro effects elicited by rAnxA1. Treatment of LSK cells with rAnxA1 led to phosphorylation of PCL gamma 2, PKC, RAS, MEK, and ERK1/2 with increased expression of NFAT2. In long-term bone marrow cultures, rAnxA1 did not alter the percentage of LSK cells but enhanced the Gr-1(+)Mac-1(+) population; treatment with a PLC (U73122), but not with a PKC (GF109203), inhibitor reduced rAnxA1-induced phosphorylation of ERK1/2 and Elk1. Therefore, we identify here rAnxA1 as an inducer of HSC/progenitor cell differentiation, favouring differentiation of the myeloid/granulocytic lineage, via Ca2+/MAPK signalling transduction pathways. (AU)

• FAPESP's process: 16/02903-6 - Role of annexin A1 in modulating granulopoiesis
• Grantee: Christiano Marcello Vaz Barbosa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 14/07328-4 - Identification of endogenous pathways for the control of inflammation
• Grantee: Sandra Helena Poliselli Farsky
• Support Opportunities: Research Projects - Thematic Grants