FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation

Itkin, T., Ludin, A., Gradus, B., Gur-Cohen, S., Kalinkovich, A., Schajnovitz, A., Ovadya, Y., Kollet, O., Canaani, J., Shezen, E., Coffin, D. J., Enikolopov, G. N., Berg, T., Piacibello, W., Hornstein, E., Lapidot, T. (August 2012) FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation. Blood, 120 (9). pp. 1843-1855. ISSN 0006-4971

URL: http://www.ncbi.nlm.nih.gov/pubmed/22645180
DOI: 10.1182/blood-2011-11-394692

Abstract

Cytokine-induced expansion of hematopoietic stem and progenitor cells (HSPCs) is not fully understood. In the present study, we show that whereas steady-state hematopoiesis is normal in basic fibroblast growth factor (FGF-2)-knockout mice, parathyroid hormone stimulation and myeloablative treatments failed to induce normal HSPC proliferation and recovery. In vivo FGF-2 treatment expanded stromal cells, including perivascular Nestin(+) supportive stromal cells, which may facilitate HSPC expansion by increasing SCF and reducing CXCL12 via mir-31 up-regulation. FGF-2 predominantly expanded a heterogeneous population of undifferentiated HSPCs, preserving and increasing durable short- and long-term repopulation potential. Mechanistically, these effects were mediated by c-Kit receptor activation, STAT5 phosphorylation, and reduction of reactive oxygen species levels. Mice harboring defective c-Kit signaling exhibited abrogated HSPC expansion in response to FGF-2 treatment, which was accompanied by elevated reactive oxygen species levels. The results of the present study reveal a novel mechanism underlying FGF-2-mediated in vivo expansion of both HSPCs and their supportive stromal cells, which may be used to improve stem cell engraftment after clinical transplantation.

Item Type: Paper
Subjects: organism description > animal
organs, tissues, organelles, cell types and functions > cell types and functions
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell

organism description > animal > mammal > rodent > mouse
organism description > animal > mammal > rodent
CSHL Authors:
Communities: CSHL labs > Enikopolov lab
CSHL Cancer Center Program > Signal Transduction
Depositing User: Matt Covey
Date: 30 August 2012
Date Deposited: 30 Jan 2013 19:13
Last Modified: 16 Oct 2015 15:43
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26969

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