| First Author | Capitano M | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 10 | Pages | 1027-1038 |
| PubMed ID | 30042096 | Mgi Jnum | J:265911 |
| Mgi Id | MGI:6201970 | Doi | 10.1182/blood-2017-09-806257 |
| Citation | Capitano M, et al. (2018) Phosphatidylinositol transfer proteins regulate megakaryocyte TGF-beta1 secretion and hematopoiesis in mice. Blood 132(10):1027-1038 |
| abstractText | We hypothesized that megakaryocyte (MK) phosphoinositide signaling mediated by phosphatidylinositol transfer proteins (PITPs) contributes to hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) regulation. Conditional knockout mice lacking PITPs specifically in MKs and platelets (pitpalpha(-/-) and pitpalpha(-/-)/beta(-/-)) bone marrow (BM) manifested decreased numbers of HSCs, MK-erythrocyte progenitors, and cycling HPCs. Further, pitpalpha(-/-)/beta(-/-) BM had significantly reduced engrafting capability in competitive transplantation and limiting dilution analysis. Conditioned media (CM) from cultured pitpalpha(-/-) and pitpalpha(-/-)/beta(-/-) BM MKs contained higher levels of transforming growth factor beta1 (TGF-beta1) and interleukin-4 (IL-4), among other myelosuppressive cytokines, than wild-type BM MKs. Correspondingly, BM flush fluid from pitpalpha(-/-) and pitpalpha(-/-)/beta(-/-) mice had higher concentrations of TGF-beta1. CM from pitpalpha(-/-) and pitpalpha(-/-)/beta(-/-) MKs significantly suppressed HPC colony formation, which was completely extinguished in vitro by neutralizing anti-TGF-beta antibody, and treatment of pitpalpha(-/-)/beta(-/-) mice in vivo with anti-TGF-beta antibodies completely reverted their defects in BM HSC and HPC numbers. TGF-beta and IL-4 synergized to inhibit HPC colony formation in vitro. Electron microscopy analysis of pitpalpha(-/-)/beta(-/-) MKs revealed ultrastructural defects with depleted alpha-granules and large, misshaped multivesicular bodies. Von Willebrand factor and thrombospondin-1, like TGF-beta, are stored in MK alpha-granules and were also elevated in CM of cultured pitpalpha(-/-)/beta(-/-) MKs. Altogether, these data show that ablating PITPs in MKs indirectly dysregulates hematopoiesis in the BM by disrupting alpha-granule physiology and secretion of TGF-beta1. |
