Mouse Flk-1+Sca-1- mesenchymal stem cells: functional plasticity in vitro and immunoregulation in vivo.
OBJECTIVE
Mesenchymal stem cells (MSCs) represent a powerful tool in regenerative medicine because of their differentiation and migration capacities. Moreover, the immunomodulatory ability of MSCs may be used to develop therapies for the treatment of autoimmune diseases.


METHODS
In this study, we isolated Flk-1Sca-1 MSCs from bone marrow (bMSCs). Next, we studied their biological characteristics and immunologic functions. We also investigated their effects on graft-versus-host disease (GVHD) associated with allogeneic bone marrow transplantation in mice.


RESULTS
Flk-1Sca-1 bMSCs were able to differentiate into fat and cartilage cells, indicating that the isolated cells had stem cell properties. They could also suppress alloantigen-induced T cell proliferation in vitro in a dose-dependent manner. Infusion of bMSCs into allogeneic bone marrow-transplanted mice alleviated the lethal GVHD that occurred in control recipient mice. There was significantly lower mortality among the recipients of the Flk-1Sca-1 bMSCs that also ameliorated the clinical symptoms and GVHD histopathology. Beneficial effects on GVHD by Flk-1Sca-1 bMSCs were also observed when MSCs were engineered to express anti-inflammatory cytokines IL-4 and IL-10 and decrease expression of proinflammatory cytokines IFN-γ, TNF-α, and IL-2.


CONCLUSIONS
Flk-1Sca-1 bMSCs have stem cell properties and can efficiently ameliorate the GVHD associated with allogeneic bone marrow transplantation in mice.
1 Institute of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China. 2 Institute of Basic medicine, Peking Union Medical College, Department of Cell Biology, Beijing 100005, China. 3 Address correspondence to: Ren Jun, Ph.D., M.D., Institute of Medical Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
Zhu
Z
Xishan
Yu
Y
Haojun
He
H
Baoxin
Zhou
Z
Xinna
Jiang
J
Ni
Zhang
Z
Hongmei
Wang
W
Xiaoli
Ren
R
Jun
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D056747:Immunomodulation / Q000502:physiology*; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013601:T-Lymphocytes / Q000473:pathology; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D000950:Antigens, Ly; D016207:Cytokines; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2