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In-vivo generation of bone via endochondral ossification by in-vitro chondrogenic priming of adult human and rat mesenchymal stem cells


Background: Bone grafts are required to repair large bone defects after tumour resection or
large trauma. The availability of patients’ own bone tissue that can be used for these
procedures is limited. Thus far bone tissue engineering has not lead to an implant which
could be used as alternative in bone replacement surgery. This is mainly due to problems of
vascularisation of the implanted tissues leading to core necrosis and implant failure. Recently
it was discovered that embryonic stem cells can form bone via the endochondral pathway,
thereby turning in-vitro created cartilage into bone in-vivo. In this study we investigated the
potential of human adult mesenchymal stem cells to form bone via the endochondral
pathway. Methods: MSCs were cultured for 28 days in chondrogenic, osteogenic or control
medium prior to implantation. To further optimise this process we induced mineralisation in
the chondrogenic constructs before implantation by changing to osteogenic medium during
the last 7 days of culture. Results: After 8 weeks of subcutaneous implantation in mice, bone
and bone marrow formation was observed in 8 of 9 constructs cultured in chondrogenic
medium. No bone was observed in any samples cultured in osteogenic medium. Switch to
osteogenic medium for 7 days prevented formation of bone in-vivo. Addition of β-
glycerophosphate to chondrogenic medium during the last 7 days in culture induced
mineralisation of the matrix and still enabled formation of bone and marrow in both human
and rat MSC cultures. To determine whether bone was formed by the host or by the
implanted tissue we used an immunocompetent transgenic rat model. Thereby we found that
osteoblasts in the bone were almost entirely of host origin but the osteocytes are of both host
and donor origin. Conclusions: The preliminary data presented in this manuscript
demonstrates that chondrogenic priming of MSCs leads to bone formation in vivo using both
human and rat cells. Furthermore, addition of β-glycerophosphate to the chondrogenic
medium did not hamper this process. Using transgenic animals we also demonstrated that both host and donor cells played a role in bone formation. In conclusion these data indicate
that in-vitro chondrogenic differentiation of human MSCs could lead to an alternative and
superior approach for bone tissue engineering.

Suggested citation:

. () In-vivo generation of bone via endochondral ossification by in-vitro chondrogenic priming of adult human and rat mesenchymal stem cells [Online]. Available from: [Accessed: 22nd September 2019].


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