Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow.
OBJECTIVE
Cytokine-mediated mobilization of hematopoietic stem cells has become an established method in the field of autologous and allogenic stem cell transplantation. Furthermore, it presents a new concept in tissue repair and regenerative medicine. In the present study, we explored the potency of parathyroid hormone (PTH) compared to granulocyte colony-stimulating factor (G-CSF) for mobilization of stem cells and its regenerative capacity on bone marrow.


METHODS
Healthy mice were either treated with PTH, G-CSF, or saline. Laboratory parameters were analyzed using a hematological cell analyzer. Hematopoietic stem cells characterized by lin(-)/Sca-1(+)/c-kit(+), as well as subpopulations (CD31(+), c-kit(+), Sca-1(+), CXCR4(+)) of CD45(+)/CD34(+) and CD45(+)/CD34(-) cells were measured by flow cytometry. Immunohistology as well as fluorescein-activated cell sorting analyses were utilized to determine the composition and cell-cycle status of bone marrow cells. Serum levels of distinct cytokines (G-CSF, vascular endothelial growth factor [VEGF]) were determined by enzyme-linked immunosorbent assay. Further, circulating cells were measured after PTH treatment in combination with G-CSF or a G-CSF antibody.


RESULTS
Stimulation with PTH showed a significant increase of all characterized subpopulations of bone marrow-derived progenitor cells (BMCs) in peripheral blood (1.5- to 9.8-fold) similar to G-CSF. In contrast to G-CSF, PTH treatment resulted in an enhanced cell proliferation with a constant level of lin(-)/Sca-1(+)/c-kit(+) cells and CD45(+)/CD34(+) subpopulations in bone marrow. Interestingly, PTH application was associated with increased serum levels of G-CSF (2.8-fold), whereas VEGF showed no significant changes. Blocking endogenous G-CSF with an antibody significantly reduced the number of circulating cells after PTH treatment. A combination of PTH and G-CSF showed slight additional effects compared to PTH or G-CSF alone.


CONCLUSIONS
PTH induces mobilization of progenitor cells effectively, which can be related to an endogenous release of G-CSF. In contrast to G-CSF treatment, PTH does not result in a depletion of bone marrow, which may be mediated by an activation of PTH receptor on osteoblasts. The novel function of PTH on mobilization and regeneration of BMCs may pave the way for new therapeutic options in bone marrow and stem cell transplantation as well as in the field of ischemic disorders.
Brunner
Stefan
S
Ludwig-Maximilians University, Klinikum Grosshadern, Medical Department I, Munich, Germany.
Zaruba
Marc-Michael
MM
Huber
Bruno
B
David
Robert
R
Vallaster
Marcus
M
Assmann
Gerald
G
Mueller-Hoecker
Josef
J
Franz
Wolfgang-Michael
WM
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000145:classification; D002453:Cell Cycle / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000494:pharmacology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D010281:Parathyroid Hormone; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016179:Granulocyte Colony-Stimulating Factor