Blood cell production in the acute settings of trauma, surgery, sepsis, sickle cell crisis and after stem cell transplant is critical for survival and yet is often dysfunctional in those settings. We have recently used a single cell, proximity based analysis to define a distinctive mesenchymal cell subpopulation in the bone marrow that differentially expresses molecules governing hematopoietic stem and progenitor quiescence. These molecules, IL-18 and angiogenin are differentially regulated with stress and we hypothesize, participate in dysfunctional hematopoiesis. We seek to define the role of these specific molecules in models of sepsis and transplant to determine if modulating them will improve blood cell production and survival. Further, we seek to extend the advantage of defining specific subsets of marrow stromal cells more broadly and propose unbiased, single cell analytic tools to define the complexity of marrow stroma and how it may be altered in settings of stress.

Public Health Relevance

Blood cell production in the acute settings of trauma, surgery, sepsis, sickle cell crisis and after stem cell transplant is critical for survival and yet, is ofte dysfunctional in those settings. This proposal seeks to investigate how stress alters the bone marrow microenvironment where blood cell production takes place. We plan to do this using molecules recently identified by us as participating in the bone marrow niche that modify the quiescence of blood cell progenitors and are modulated under conditions of stress.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK107784-04
Application #
9624767
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bishop, Terry Rogers
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
Petukhov, Viktor; Guo, Jimin; Baryawno, Ninib et al. (2018) dropEst: pipeline for accurate estimation of molecular counts in droplet-based single-cell RNA-seq experiments. Genome Biol 19:78
Goncalves, Kevin A; Silberstein, Lev; Li, Shuping et al. (2016) Angiogenin Promotes Hematopoietic Regeneration by Dichotomously Regulating Quiescence of Stem and Progenitor Cells. Cell 166:894-906
Silberstein, Lev; Goncalves, Kevin A; Kharchenko, Peter V et al. (2016) Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators. Cell Stem Cell 19:530-543