Murine but Not Human Mesenchymal Stem Cells Generate Osteosarcoma-Like Lesions in the Lung

Abstract

Murine mesenchymal stem cells are capable of differentiation into multiple cell types both in vitro and in vivo and may be good candidates to use as cell therapy for diseased or damaged organs. We have previously reported a method of enriching a population of murine MSCs that demonstrated a diverse differentiation potential both in vitro and in vivo. In this study, we show that this enriched population of murine mesenchymal stem cells embolize within lung capillaries following systemic injection and then rapidly expand within, and invade into, the lung parenchyma, forming tumor nodules. These lesions rarely contain cells bearing the immunohistochemical characteristics of lung epithelium, but they do show the characteristics of immature bone and cartilage that resembles exuberant fracture callus or well-differentiated osteosarcoma. Our findings indicate that murine mesenchymal stem cells can behave in a manner similar to tumor cells, with dysregulated growth and aberrant differentiation within the alveolar microenvironment after four passages. We demonstrate that unlike human MSCs, MSCs from different mouse strains can acquire chromosomal abnormalities after only a few in vitro passages. Moreover, other parameters, such as mouse strain used, might also play a role in the induction of these tumors. These findings might be clinically relevant for future stem cell therapy studies. STEM CELLS 2007;25:1586 -1594 Disclosure of potential conflicts of interest is found at the end of this article.

FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells

“…Similar to our data, the expression of EWS-FLI-1 was able to transform BM-mMSC [3] but unable to transform BM-hMSCs although it induced a gene expression profile resembling features of Ewing's Sarcomas [7]. Moreover, mMSCs but not hMSCs generated osteosarcoma-like lesions in the lung following systemic injection in mice [48]. These data confirm that mMSCs are much more susceptible to transformation and sarcoma development [49] than hMSCs, which seem to require additional cooperating mutations to constitute a useful cellular model for sarcomagenesis.…”

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

“…The resulting MSC, when implanted into immunecompromised mice using hydroxyapatite/tricalcium phosphate as a carrier, as well as when injected into the tail vein led to sarcoma formation (Miura et al, 2006). Murine MSC also rapidly acquire chromosomal abnormalities in culture, and after infusion, these cells invaded lung parenchyma and formed tumor nodules with the characteristics of differentiated osteosarcomas (Aguilar et al, 2007). Compared to murine MSC, human MSC in long-term culture greatly differ in their behavior.…”

Murine bone marrow derived stromal progenitor cells fail to prevent or treat acute graft‐versus‐host disease

“…Furthermore, the immunosuppressive effects of human SPC are more potent, with effects seen at much lower SPC to responder ratios than required for similar murine SPC studies. (Di Nicola et al, 2002;Krampera et al, 2003) There are also cell dose limitations with intravenous administration of murine SPCs due to acute pulmonary embolism (Gao et al, 2001;Aguilar et al, 2007) related to their smaller pulmonary vascular bed. This limited our ability to administer even higher doses of SPCs to assess dose effects.…”