TY - JOUR
T1 - FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation
AU - Itkin, Tomer
AU - Ludin, Aya
AU - Gradus, Ben
AU - Gur-Cohen, Shiri
AU - Kalinkovich, Alexander
AU - Schajnovitz, Amir
AU - Ovadya, Yossi
AU - Kollet, Orit
AU - Canaani, Jonathan
AU - Shezen, Elias
AU - Coffin, Douglas J.
AU - Enikolopov, Grigori N.
AU - Berg, Thorsten
AU - Piacibello, Wanda
AU - Hornstein, Eran
AU - Lapidot, Tsvee
N1 - Israeli Science Foundation [544/09]; European Union (Advance Cell-based Therapies for the Treatment of Primary Immunodeficiency [HEALTH-F5-2010-261387]; Edith Arnoff Stein Professorial Chair in Stem Cell ResearchThis study was supported in part by the Israeli Science Foundation (544/09), the European Union (Advance Cell-based Therapies for the Treatment of Primary Immunodeficiency HEALTH-F5-2010-261387), and The Edith Arnoff Stein Professorial Chair in Stem Cell Research (T.L.). The work of T.B. was generously supported by the Department of Molecular Biology (director Axel Ullrich) at the Max Planck Institute of Biochemistry.
PY - 2012/8/30
Y1 - 2012/8/30
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84865786049&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood-2011-11-394692
DO - https://doi.org/10.1182/blood-2011-11-394692
M3 - مقالة
C2 - 22645180
SN - 0006-4971
VL - 120
SP - 1843
EP - 1855
JO - Blood
JF - Blood
IS - 9
ER -