Mouse Flk-1+Sca-1- mesenchymal stem cells: functional plasticity in vitro and immunoregulation in vivo.

OBJECTIVES: 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. CONCLUSION: Flk-1Sca-1 bMSCs have stem cell properties and can efficiently ameliorate the GVHD associated with allogeneic bone marrow transplantation in mice.

Comparison of the effects of human adipose and bone marrow mesenchymal stem cells on T lymphocytes.

Mesenchymal stem cells (MSCs) are multipotent cells that can be derived either from the bone marrow (bMSCs) or adipose tissue (aMSCs). We have compared the immune regulatory properties of cells derived from bone marrow and adipose tissue to provide a theoretical basis for the choice of stem cell source for transplantation. The phenotypes of bMSCs and aMSCs are similar, differing only in the expression of CD106. aMSCs proliferate faster than bMSCs, but aMSCs suppressed T-lymphocyte proliferation and activation more poorly than bMSCs. Thus cell origin and abundance are important factors in determining the suitability of MSCs for transplantation. Adipose tissue offers a more promising source of cells for such an application.

Impaired immunomodulatory function of chronic myeloid leukemia cancer stem cells and the possible mechanism involved in it.

BACKGROUND: Cancer stem cells (CSCs) are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Development of specific therapies targeted at CSCs holds hope for the improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease. This is particularly true in chronic myeloid leukemia (CML). METHODS: In this study, we isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Philadelphia chromosome-positive (Ph(+)) patients with stem cells property. We examined their biological characteristics as well as immunological function and further detected the possible molecular mechanism involved in the leukemia genesis. RESULTS: We showed that CML patient-derived Flk1(+)CD31(-)CD34(-) MSCs had normal morphology, phenotype and karyotype but appeared impaired immunomodulatory function. The capacity of Flk1(+)CD31(-)CD34(-) MSCs from CML patients to inhibit T lymphocyte activation and proliferation was impaired in vitro. CML patient-derived MSCs have dampening immunomodulatory functions, suggesting that the dysregulation of hematopoiesis and immune response might originate from MSCs rather than HSCs. These Ph(+) putative CML hemangioblast upregulated TGF-ß1 and resultantly activated matrix metalloproteinase-9 (MMP-9) to enhance s-KitL and s-ICAM-1 secretion, which activated c-kit(+) HSCs from the quiescent state to proliferative state. Further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/nuclear factor (NF)-κB signaling pathway was involved in CML pathogenesis. CONCLUSIONS: Flk1(+)CD31(-)CD34(-) MSCs that express BCR/ABL leukemia oncogene are CSCs of CML and they play a critical role in the progression of CML through PI3K/Akt/NF-κB/MMP-9/s-ICAM-1/s-KitL signaling pathway beyond HSCs.