Other
18 Authors
- Gupta S,
- Lazarus AH,
- Branch DR,
- Neves MAD,
- Carrim N,
- Ni H,
- Kunishima S,
- Rotstein O,
- Zhu G,
- Hou M,
- Yu R,
- Li J,
- Xu M,
- Ruggeri ZM,
- Peng J,
- Marshall J,
- Ware J,
- Freedman J
| First Author | Xu M | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 6 | Pages | 622-634 |
| PubMed ID | 29794068 | Mgi Jnum | J:266091 |
| Mgi Id | MGI:6201951 | Doi | 10.1182/blood-2017-12-820779 |
| Citation | Xu M, et al. (2018) GPIbalpha is required for platelet-mediated hepatic thrombopoietin generation. Blood 132(6):622-634 |
| abstractText | Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbalpha(-/-) mice compared with wild-type (WT) controls, which was consistent in GPIbalpha-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbalpha-deficient conditions were not due to increased TPO clearance by GPIbalpha(-/-) platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbalpha(-/-), platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbalpha(-/-) mice. In vitro hepatocyte cocultures with platelets or GPIbalpha-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbalpha. Treatment of GPIbalpha(-/-) platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbalpha(-/-) platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbalpha, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIbalpha-transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbalpha, demonstrating that the N terminus of GPIbalpha is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbalpha, such as BSS and auto- and alloimmune-mediated thrombocytopenias. |
