In vitro expanded bone marrow-derived murine (C57Bl/KaLwRij) mesenchymal stem cells can acquire CD34 expression and induce sarcoma formation in vivo

Mesenchymal stem cells (MSCs) have currently generated numerous interests in pre-clinical and clinical applications due to their multiple lineages differentiation potential and immunomodulary effects. However, accumulating evidence indicates that MSCs, especially murine MSCs (mMSCs), can undergo spontaneous transformation after long-term in vitro culturing, which might reduce the therapeutic application possibilities of these stem cells. In the present study, we observed that in vitro expanded bone marrow (BM) derived mMSCs from the C57Bl/KaLwRij mouse strain can lose their specific stem cells markers (CD90 and CD105) and acquire CD34 expression, accompanied with an altered morphology and an impaired tri-lineages differentiation capacity. Compared to normal mMSCs, these transformed mMSCs exhibited an increased proliferation rate, an enhanced colony formation and migration ability as well as a higher sensitivity to anti-tumor drugs. Transformed mMSCs were highly tumorigenic in vivo, resulting in aggressive sarcoma formation when transplanted in non-immunocompromised mice. Furthermore, we found that Notch signaling downstream genes (hey1, hey2 and heyL) were significantly upregulated in transformed mMSCs, while Hedgehog signaling downstream genes Gli1 and Ptch1 and the Wnt signaling downstream gene beta-catenin were all decreased. Taken together, we observed that murine in vitro expanded BM-MSCs can transform into CD34 expressing cells that induce sarcoma formation in vivo. We assume that dysregulation of the Notch(+)/Hh(−)/Wnt(−) signaling pathway is associated with the malignant phenotype of the transformed mMSCs.

► Murine MSCs can undergo spontaneously malignant transformation and form sarcoma.
► Acquisition of CD34 is a transformation type for MSCs into sarcoma.
► Notch/Hh/Wnt pathways are related to the malignant phenotype of transformed MSCs.