Journal article
KRas(G12D) expression in the bone marrow vascular niche affects hematopoiesis with inflammatory signals
Experimental hematology, Vol.79, pp.3-15
11/01/2019
DOI: 10.1016/j.exphem.2019.10.003
PMCID: PMC6921092
PMID: 31669153
Abstract
The bone marrow (BM) niche is an important milieu where hematopoietic stem and progenitor cells (HSPCs) are maintained. Previous studies have indicated that genetic mutations in various components of the niche can affect hematopoiesis and promote hematologic abnormalities, but the impact of abnormal BM endothelial cells (BMECs), a crucial niche component, on hematopoiesis remains incompletely understood. To dissect how genetic alterations in BMECs could affect hematopoiesis, we have employed a novel inducible Tie2-CreERT2 mouse model, with a tdTomato fluorescent reporter, to introduce an oncogenic KRas(G12D) mutation specifically in the adult endothelial cells. Tie2-CreERT2;KRas(G12D )mice had significantly more leukocytes and myeloid cells in the blood with mostly normal BM HSPC populations and developed splenomegaly. Genotyping polymerase chain reaction revealed KRas(G12D) activation in BMECs but not hematopoietic cells, confirming that the phenotype is due to the aberrant BMECs. Competitive transplant assays revealed that BM cells from the KRas(G12D) mice contained significantly fewer functional hematopoietic stem cells, and immunofluorescence imaging showed that the hematopoietic stem cells in the mutant mice were localized farther away from BM vasculature and closer to the endosteal area. RNA sequencing analyses found an inflammatory gene network, especially tumor necrosis factor a, as a possible contributor. Together, our results implicate an abnormal endothelial niche in compromising normal hematopoiesis. (C) 2019 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Details
- Title: Subtitle
- KRas(G12D) expression in the bone marrow vascular niche affects hematopoiesis with inflammatory signals
- Creators
- Cindy L. Hochstetler - Cincinnati Children's Hospital Medical CenterYuxin Feng - Cincinnati Children's Hospital Medical CenterMehmet Sacma - Universität UlmAshley K. Davis - Cincinnati Children's Hospital Medical CenterMahil Rao - Stanford UniversityChia-Yi Kuan - University of VirginiaLi-Ru You - Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei, TaiwanHartmut Geiger - Cincinnati Children's Hospital Medical CenterYi Zheng - University of Cincinnati
- Resource Type
- Journal article
- Publication Details
- Experimental hematology, Vol.79, pp.3-15
- DOI
- 10.1016/j.exphem.2019.10.003
- PMID
- 31669153
- PMCID
- PMC6921092
- NLM abbreviation
- Exp Hematol
- ISSN
- 0301-472X
- eISSN
- 1873-2399
- Publisher
- Elsevier
- Number of pages
- 13
- Grant note
- RO1 DK104814; R01 CA204895; R01 HL134617 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32ES007250 / National Institute of Environmental Health Sciences; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) F31HL136229 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Cancer Free Kids grant R01DK104814 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01CA204895 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 11/01/2019
- Academic Unit
- Critical Care; Stead Family Department of Pediatrics
- Record Identifier
- 9984775023602771
Metrics
4 Record Views