The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner.
BACKGROUND
Recently we identified in bone marrow (BM) by employing chemotactic isolation to SDF-1 gradient combined with real time RT-PCR analysis a mobile population of CXCR4+ BM mononuclear cells that express mRNA for various markers of early tissue-committed stem cells (TCSCs). In this study we evaluated whether TCSCs respond to other motomorphogens, such as hepatocyte growth factor (HGF) and leukemia inhibitory factor (LIF).


METHODS
We again employed chemotactic isolation combined with real-time RT-PCR analysis to assess whether murine and human BM contain TCSCs that respond to HGF and LIF gradients. We also evaluated expressions of HGF and LIF in damaged organs.


RESULTS
We noted that the number of TCSCs is highest in BM from young (1- to 2-month-old) mice and decreases in 1-year-old animals. Murine and human TCSCs 1) respond to HGF and LIF gradients in addition to an SDF-1 gradient, 2) reside in populations of BM-derived non-hematopoietic CD45-cells, and 3) are released (mobilized) from BM into the peripheral blood (PB) during tissue injury (e.g. after partial body irradiation).


CONCLUSIONS
These findings further support our theory of the BM as a "hideout" for TCSCs and we suggest that their presence in BM tissue should be considered before experimental evidence is interpreted simply as transdifferentiation/plasticity of hematopoietic stem cells. Since we demonstrated that not only SDF-1, but also HGF and LIF are upregulated in damaged tissues, we postulate that CXCR4+ c-Met+ LIF-R+ TCSC could be mobilized from the BM into the PB, from which they are subsequently chemoattracted to damaged organs, where they play a role in tissue repair/regeneration.
Kucia
Magda
M
Stem Cell Biology Program at the James Graham Brown Cancer Center, University of Louisville, 529 South Jackson Street, Louisville, KY 40202, USA.
Wojakowski
Wojtek
W
Reca
Ryan
R
Machalinski
Bogdan
B
Gozdzik
Jolanta
J
Majka
Marcin
M
Baran
Jarek
J
Ratajczak
Janina
J
Ratajczak
Mariusz Z
MZ
D000367:Age Factors; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000502:physiology; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D017493:Leukocyte Common Antigens / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D053606:Receptors, OSM-LIF; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D015850:Interleukin-6; C507837:LIF protein, human; C507840:LIFR protein, human; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; D019718:Receptors, CXCR4; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D017493:Leukocyte Common Antigens