Background and Objectives
Mesenchymal stem cells (MSC) are adult stem cells that can be expanded many fold
in vitro and have the therapeutic potential to restore the bone marrow microenvironment
and support hematopoietic recovery after myeloablative conditioning for
hematopoietic stem cell transplantation. Successful homing to the target tissue, such
as bone marrow, implies that MSC are able to extravasate after systemic administration.
However, the extravasation capacity of MSC and the underlying mechanisms are
poorly understood to date. We studied in vitro the capacity of MSC to migrate through
bone marrow endothelium.
Design and Methods
In vitro invasion and transendothelial migration assays were performed. The expression
of matrix metalloproteinase (MMP) was analyzed by reverse transcriptase polymerase
chain reaction (RT-PCR) and zymography. Migration of cells cultured at high or
low confluence was compared and differential gene expression in these conditions
was analyzed with microarray and real-time RT-PCR. The functional involvement in
MSC migration was assessed using neutralizing anti-MMP-2 antibody, MMP-2 short
interfering RNA or recombinant tissue inhibitor of metalloproteinase (TIMP-3).
We demonstrated that MSC can invade reconstituted basement membrane and that
bone marrow endothelial cells stimulate this process. We also showed that the
transendothelial migration of MSC is at least partially regulated by MMP-2. High culture
confluence was found to increase production of the natural MMP-inhibitor TIMP-
3 and decrease transendothelial migration of MSC.
Interpretation and Conclusions
We show that MSC have the potential to migrate through bone marrow endothelium
and that this process involves MMP-2. Moreover, the migration of MSC is significantly
influenced by the level of culture confluence. Increased culture confluence impairs
migration and is related to an upregulation of TIMP-3. The therapeutic use of MSC
would benefit from a selection of culture conditions that allow optimal extravasation
of these cells.
Original languageEnglish
Pages (from-to)440-449
Number of pages10
JournalHaematologica: the Haematology Journal
Issue number2007
Publication statusPublished - 2007

    Research areas

  • HUMAN MESENCHYMAL STEM CELLS, migration, culture confluence, MMP-2, TIMP-3

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