Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the peripheral blood has made harvest of donor cells for bone marrow (BM) transplantations more convenient and improved cell yield and engraftment. HSPC mobilization by G-CSF (Filgrastim) is mediated by modulation of the stem cell niche, which is the BM microenvironment that retains and regulates HSPCs. There have been many hints in the literature that monocytes and macrophages control the hematopoietic niche. This application proposes to study the role of the M-CSF receptor (CD115)-expressing cells in the maintenance of the HSC niche. Our preliminary data indicates that G-CSF reduces BM monocyte and macrophage numbers and in vivo depletion of these populations is correlated with HSPC mobilization and reduction in BM CXCL12, an HSPC retention chemokine. In this proposal, 1 will a) confirm this correlation in two additional in vivo models of CD115+ cell depletion, b) identify the factors mediating cross-talk (via microarray of CD115+ cells co-cultured with a murine BM-derived stromal cell line and protein array of culture supernatant), c) determine dependence of CDI 15-depletion-induced mobilization of HSPC on the sympathetic nervous system (using pharmacological, surgical and genetic models of sympathectomy), and d) elucidate synergy of this mobilization with other mobilizing agents (G-CSF and AMD3100).
For aims a, c, d, e, I will assess HSPC mobilization by colony forming assays, CD115+ cell reduction by flow cytometry, and reduction in CXCL12 chemokine by ELISA.

Public Health Relevance

While stem cell mobilization has made retrieval of donor cells for transplants more convenient and efficient, it yields an insufficient number of stem cells in up to 40% of patients. The experiments proposed can potentially lead to the development of new strategies targeting the BM monocytes and macrophages to maximize stem cell yield. The results of this project also has broad implications for the maintenance of non-hematopoietic stem cell niches, whose manipulation can be instrumental in facilitating tissue repair after injuries, such as myocardial infarction, traumatic burns, and neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL099028-03
Application #
8209164
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Mitchell, Phyllis
Project Start
2010-01-12
Project End
2012-07-12
Budget Start
2012-01-12
Budget End
2012-07-12
Support Year
3
Fiscal Year
2012
Total Cost
$17,417
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Hashimoto, Daigo; Chow, Andrew; Noizat, Clara et al. (2013) Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38:792-804
Chow, Andrew; Huggins, Matthew; Ahmed, Jalal et al. (2013) CD169ýýý macrophages provide a niche promoting erythropoiesis under homeostasis and stress. Nat Med 19:429-36
Chow, Andrew; Lucas, Daniel; Hidalgo, Andres et al. (2011) Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med 208:261-71