Acute inflammatory signals associated with infection lead to HSC proliferation thus generating large numbers of immune effector cells. However, more severe and prolonged inflammation has been linked to bone marrow failure states, e.g. complications following bone marrow transplantation. Infectious as well as non-infectious inflammatory signals affect HSC homeostasis. Such effects can be mediated directly on HSC or indirectly via niche cells. CXCL12-expressing niche cells represent an important niche cell population forming distinct niches that support hematopoietic stem and/or progenitor cells. Utilizing complementary novel imaging approaches for 2D and 3D analysis of the bone marrow cavity, we show that inflammatory stress following administration of TNF-? and/or lipopolysaccharide (LPS) rapidly reduces the number of CXCL12 expressing niche cells and causes defects in niche cell cytoplasmic structure within 1-4 hours. We propose that understanding how inflammatory signals modulate HSCP niche cells may implicate a pathogenic role of niche cells in disorders of dysfunctional hematopoiesis associated with inflammation in the peri-transplant setting.
In Aim 1 we will delineate the consequences of inflammation on CXCL12-niche cell number and/or growth factor expression in specific CXCL12 expressing niche cell populations. The analyses will be done at various time intervals following administration of TNF-?, LPS.
In aim 2, the dynamic alterations in CXCL12 expressing niche cell cytoplasmic structure will be visualized and quantified at different time intervals by three complementary imaging techniques. The dynamic structural changes will be correlated with hematopoietic cellularity in BM and egress into the circulation.
In aim 3, we will examine whether LPS and TNF-? mediate their effect on hematopoiesis directly or indirectly (e.g. by acting first on hematopoietic cells such as macrophages). To this end, 4 separate reconstituted chimeric mice in which the hematopoietic compartment/bone marrow microenvironment is either WT or deficient in TNFR/TLR4, will be generated. We propose that understanding the dynamic relationship between stromal cells and HSPC following inflammatory stress may lead to new therapeutic approaches for hematopoietic regeneration in bone marrow dysfunction states in the peri- transplant setting, which require significant blood product support.

Public Health Relevance

/Relevance Inflammation is linked to several bone marrow failure syndromes, which require significant transfusion support. This grant will investigate how inflammatory signals influence bone marrow niche cells leading to impaired hematopoiesis, e.g. associated with hematopoietic stem cell transplantation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Mondoro, Traci
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Children's Hospital
United States
Zip Code
Liu, Bee Hui; Jobichen, Chacko; Chia, C S Brian et al. (2018) Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proc Natl Acad Sci U S A 115:E7119-E7128
Karatepe, Kutay; Zhu, Haiyan; Zhang, Xiaoyu et al. (2018) Proteinase 3 Limits the Number of Hematopoietic Stem and Progenitor Cells in Murine Bone Marrow. Stem Cell Reports 11:1092-1105
Liu, Ning-Ning; Uppuluri, Priya; Broggi, Achille et al. (2018) Intersection of phosphate transport, oxidative stress and TOR signalling in Candida albicans virulence. PLoS Pathog 14:e1007076
Kanneganti, Apurva; Malireddi, R K Subbarao; Saavedra, Pedro H V et al. (2018) GSDMD is critical for autoinflammatory pathology in a mouse model of Familial Mediterranean Fever. J Exp Med 215:1519-1529
Kambara, Hiroto; Liu, Fei; Zhang, Xiaoyu et al. (2018) Gasdermin D Exerts Anti-inflammatory Effects by Promoting Neutrophil Death. Cell Rep 22:2924-2936
Hou, Qingming; Liu, Fei; Chakraborty, Anutosh et al. (2018) Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. Sci Transl Med 10:
Zhang, Xue; Liu, Peng; Zhang, Christie et al. (2017) Positive Regulation of Interleukin-1? Bioactivity by Physiological ROS-Mediated Cysteine S-Glutathionylation. Cell Rep 20:224-235
Liu, Shutong; de Castro, Luis F; Jin, Ping et al. (2017) Manufacturing Differences Affect Human Bone Marrow Stromal Cell Characteristics and Function: Comparison of Production Methods and Products from Multiple Centers. Sci Rep 7:46731
Zhu, Haiyan; Kwak, Hyun-Jeong; Liu, Peng et al. (2017) Reactive Oxygen Species-Producing Myeloid Cells Act as a Bone Marrow Niche for Sterile Inflammation-Induced Reactive Granulopoiesis. J Immunol 198:2854-2864
Teng, Yan; Luo, Hongbo R; Kambara, Hiroto (2017) Heterogeneity of neutrophil spontaneous death. Am J Hematol 92:E156-E159

Showing the most recent 10 out of 46 publications