TFPI from erythroblasts drives heme production in central macrophages promoting erythropoiesis in polycythemia.

Bleeding and thrombosis are known as common complications of polycythemia for a long time. However, the role of coagulation system in erythropoiesis is unclear. Here, we discover that an anticoagulant protein tissue factor pathway inhibitor (TFPI) plays an essential role in erythropoiesis via the control of heme biosynthesis in central macrophages. TFPI levels are elevated in erythroblasts of human erythroblastic islands with JAK2V617F mutation and hypoxia condition. Erythroid lineage-specific knockout TFPI results in impaired erythropoiesis through decreasing ferrochelatase expression and heme biosynthesis in central macrophages. Mechanistically, the TFPI interacts with thrombomodulin to promote the downstream ERK1/2-GATA1 signaling pathway to induce heme biosynthesis in central macrophages. Furthermore, TFPI blockade impairs human erythropoiesis in vitro, and normalizes the erythroid compartment in mice with polycythemia. These results show that erythroblast-derived TFPI plays an important role in the regulation of erythropoiesis and reveal an interplay between erythroblasts and central macrophages.

Meteorin links the bone marrow hypoxic state to hematopoietic stem/progenitor cell mobilization.

Hematopoietic stem/progenitor cells (HSPCs) are supported and regulated by niche cells in the bone marrow with an important characterization of physiological hypoxia. However, how hypoxia regulates HSPCs is still unclear. Here, we find that meteorin (Metrn) from hypoxic macrophages restrains HSPC mobilization. Hypoxia-induced factor 1α and Yin Yang 1 induce the high expression of Metrn in macrophages, and macrophage-specific Metrn knockout increases HSPC mobilization through modulating HSPC proliferation and migration. Mechanistically, Metrn interacts with its receptor 5-hydroxytryptamine receptor 2b (Htr2b) to regulate the reactive oxygen species levels in HSPCs through targeting phospholipase C signaling. The reactive oxygen species levels are reduced in HSPCs of macrophage-specific Metrn knockout mice with activated phospholipase C signaling. Targeting the Metrn/Htr2b axis could therefore be a potential strategy to improve HSPC mobilization for stem cell-based therapy.

2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one-triphenyl-phosphine oxide (1/1).

In the title compound, C(20)H(15)N(3)O(2)·C(18)H(15)OP, the pyrimidinone heterocycle and the fused phenyl ring are inclined at 1.92 (7)°. Only the hy-droxy group is involved in hydrogen bonding, whereas the amino group is shielded from potential acceptors.

2-Anilino-3-(2-hy-droxy-phen-yl)quinazolin-4(3H)-one methanol monosolvate.

In the title compound, C(20)H(15)N(3)O(2)·CH(3)OH, the quinazolin-one ring system is approximately planar, the dihedral angle between the pyrimidinone ring and the adjacent benzene ring being 1.73 (6)°. The pyrimidinone ring makes dihedral angles of 77.58 (6) and 29.62 (6)°, respectively, with the hy-droxy-phenyl and phenyl rings. In the crystal, the components are connected by O-H⋯O and C-H⋯O hydrogen bonds, forming a zigzag chain along the b axis.

Ethyl 3-{[(3-methyl-anilino)(1H-1,2,4-triazol-1-yl)methyl-idene]amino}-1-benzofuran-2-carboxyl-ate.

The crystal structure of the title compound, C(21)H(19)N(5)O(3), is stabilized by inter-molecular N-H⋯N and C-H⋯O hydrogen bonds. The mol-ecule contains a planar [maximum deviations = -0.026 (1) and 0.027 (2) Å] benzofuran ring system, which forms dihedral angles of 78.75 (8) and 39.78 (7)° with the benzene and triazole rings, respectively.

3-(4-Fluoro-phen-yl)-2-(2-naphth-yloxy)-4-oxo-5-phenyl-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile.

The title compound, C(29)H(17)FN(4)O(2), may be used as a new precursor for obtaining bioactive mol-ecules. There are two crystallographically independent mol-ecules in the asymmetric unit. The phenyl ring, 4-fluoro-phenyl ring and 2-naphth-yloxy ring are twisted with respect to the pyrrolopyrimidine ring by 52.30 (11)/49.05 (11), 80.94 (10)/88.36 (10) and 60.58 (7)/83.76 (7)°, respectively. The crystal packing is stabilized by weak C-H⋯N hydrogen bonds.

3-Benzyl-6-isopropyl-5-phen-oxy-3H-1,2,3-triazolo[4,5-d]pyrimidin-7(6H)-one.

In the title compound, C(20)H(19)N(5)O(2), all atoms of the 1,2,3-triazolo[4,5-d]pyrimidine ring system are essentially coplanar [maximum deviation = 0.015 (2) Å], indicating the existence of a conjugate system in which each carbon and nitrogen atom is sp(2) hybridized and ten π electrons (three from carbon atoms and seven from nitrogen atoms) constitute an aromatic heterocycle. The ring system forms dihedral angles of 68.37 (10) and 71.57 (9)° with the phenyl rings. The crystal packing is stabilized by van der Waals inter-actions and intermolecular C-H⋯π interactions.

6-Allyl-3-(6-chloro-3-pyridylmeth-yl)-6,7-dihydro-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-imine.

The title compound, C(13)H(12)ClN(7), crystallizes with two independent mol-ecules in the asymmetric unit, each with similar geometries. The dihedral angles between the triazole and pyrimidine rings are 0.45 (9) and 1.00 (10)° in the two mol-ecules. A number of N-H⋯N hydrogen bonds co-operate with C-H⋯N contacts, forming a supra-molecular array in the ab plane. C-H⋯π inter-actions are also present. One of the vinyl groups was found to be disordered so that the C(H)=CH(2) atoms were resolved over two positions with the major component having a site occupancy factor of 0.539 (4).