Novel Roles for Podocalyxin in Regulating Stress Myelopoiesis, Rap1a and Neutrophil Migration
| Autor: | Kailin Xu, Aldona Karaczyn, Calvin P.H. Vary, Rose McGlauflin, Don M. Wojchowski, Amanda J. Favreau-Lessard, Pan Li, Pradeep Sathyanarayana, Edward Jachimowicz |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Neutrophils Sialoglycoproteins Biology Granulocyte Article 03 medical and health sciences chemistry.chemical_compound Mice Stress Physiological Gene Order Granulocyte Colony-Stimulating Factor Genetics medicine Animals Humans Peripheral blood cell Progenitor cell Molecular Biology Mice Knockout Myelopoiesis Monocyte Gene Expression Profiling rap1 GTP-Binding Proteins Cell Biology Hematology Hematopoietic Stem Cells Cell biology Haematopoiesis 030104 developmental biology medicine.anatomical_structure Podocalyxin chemistry Gene Expression Regulation Genetic Loci Immunology Bone marrow |
| Popis: | Podocalyxin (Podxl) is a CD34 orthologue and cell surface sialomucin reported to have roles in renal podocyte diaphragm slit development; vascular cell integrity; and the progression of blood, breast, and prostate cancers. Roles for Podxl during nonmalignant hematopoiesis, however, are largely undefined. We have developed a Vav–Cre Podxl knockout (KO) mouse model, and report on novel roles for Podxl in governing stress myelopoiesis. At steady state, Podxl expression among hematopoietic progenitor cells was low level but was induced by granulocyte colony-stimulating factor (G-CSF) in myeloid progenitors and by thrombopoietin in human stem cells. In keeping with low-level Podxl expression at steady state, Vav–Cre deletion of Podxl did not markedly alter peripheral blood cell levels. A G-CSF challenge in Podxl-KO mice, in contrast, hyperelevated peripheral blood neutrophil and monocyte levels. Podxl-KO also substantially heightened neutrophil levels after 5-fluorouracil myeloablation. These loss-of-function phenotypes were selective, and Podxl-KO did not alter lymphocyte, basophil, or eosinophil levels. Within bone marrow (and after G-CSF challenge), Podxl deletion moderately decreased colony forming units—granulocytes, eyrthrocytes, monocyte/macrophages, megakaryocytes and CD16/32 pos CD11b pos progenitors but did not affect Gr-1 pos cell populations. Notably, Podxl-KO did significantly heighten peripheral blood neutrophil migration capacities. To interrogate Podxl's action mechanisms, a co-immunoprecipitation plus liquid chromatography–mass spectrometry approach was applied using hematopoietic progenitors from G-CSF-challenged mice. Rap1a, a Ras-related small GTPase, was a predominant co-retrieved Podxl partner. In bone marrow human progenitor cells, Podxl-KO led to heightened G-CSF activation of Rap1a GTP , and Rap1a GTP inhibition attenuated Podxl-KO neutrophil migration. Studies have revealed novel roles for Podxl as an important modulator of neutrophil and monocyte formation and of Rap1a activation during stress hematopoiesis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|