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

Tomer Itkin, Aya Ludin, Ben Gradus, Shiri Gur-Cohen, Alexander Kalinkovich, Amir Schajnovitz, Yossi Ovadya, Orit Kollet, Jonathan Canaani, Elias Shezen, Douglas J. Coffin, Grigori N. Enikolopov, Thorsten Berg, Wanda Piacibello, Eran Hornstein, Tsvee Lapidot*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1843-1855
Number of pages13
JournalBlood
Volume120
Issue number9
DOIs
StatePublished - 30 Aug 2012
Externally publishedYes

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