TY - JOUR
T1 - Extracellular annexin-A1 promotes myeloid/granulocytic differentiation of hematopoietic stem/progenitor cells via the Ca2+/MAPK signalling transduction pathway
AU - Barbosa, Christiano M.
AU - Fock, Ricardo Ambrosio
AU - Hastreiter, Araceli Aparecida
AU - Reutelingsperger, Cris
AU - Perretti, Mauro
AU - Paredes-Gamero, Edgar J.
AU - Farsky, Sandra H. P.
N1 - Funding Information:
This work was funded by Fundação de Amparo a Pesquisa do Estado de São Paulo (to S.H.P.F. FAPESP—Grant 2014/07328–4; and Post doctoral fellow to C. M.V.B.—Grant 2016/02903–6). S.H.P.F. and R.A.F. are fellows of the Conselho Nacional de Pesquisa e Tecnologia (CNPq).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/9/23
Y1 - 2019/9/23
N2 - 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.
AB - 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.
KW - FORMYL-PEPTIDE RECEPTOR
KW - LINEAGE COMMITMENT
KW - LYMPH-NODES
KW - NEUTROPHILS
KW - STEM
KW - NOTCH
KW - A1
KW - ACTIVATION
KW - RESOLUTION
KW - IDENTIFICATION
U2 - 10.1038/s41420-019-0215-1
DO - 10.1038/s41420-019-0215-1
M3 - Article
C2 - 31552142
VL - 5
JO - Cell death discovery
JF - Cell death discovery
M1 - 135
ER -