Abstract
Mesenchymal stem cells (MSCs) are multipotent, tissue-resident cells that can facilitate tissue regeneration and thus, show great promise as potential therapeutic agents. Functional MSCs have been isolated and characterized from a wide array of adult tissues and are universally identified by the shared expression of a core panel of MSCs markers. One of these markers is the multifunctional cell surface peptidase CD13 that has been shown to be expressed on human and murine MSCs from many tissues. To investigate whether this universal expression indicates a functional role for CD13 in MSC biology we isolated, expanded and characterized MSCs from bone marrow of wild type (WT) and CD13KO mice. Characterization of these cells demonstrated that both WT and CD13KO MSCs expressed the full complement of MSC markers (CD29, CD44, CD49e, CD105, Sca1), showed comparable proliferation rates and were capable of differentiating toward the adipogenic and osteogenic lineages. However, MSCs lacking CD13 were unable to differentiate into vascular cells, consistent with our previous characterization of CD13 as an angiogenic regulator. Compared to WT MSCs, adhesion and migration on various extracellular matrices of CD13KO MSCs were significantly impaired, which correlated with decreased phospho-FAK levels and cytoskeletal alterations. Crosslinking human MSCs with activating CD13 antibodies increased cell adhesion to endothelial monolayers and induced FAK activation in a time dependent manner. In agreement with these in vitro data, intramuscular injection of CD13KO MSCs in a model of severe ischemic limb injury resulted in significantly poorer perfusion, decreased ambulation, increased necrosis and impaired vascularization compared to those receiving WT MSCs. This study suggests that CD13 regulates FAK activation to promote MSC adhesion and migration, thus, contributing to MSC-mediated tissue repair. CD13 may present a viable target to enhance the efficacy of mesenchymal stem cell therapies.
Highlights
Stem cells have the amazing capacity to contribute to the growth and healing of many different types of tissues and hold tremendous promise as therapeutic tools in many diseases
To determine if CD13 contributes to the biologic function of stem cells we isolated Mesenchymal stem cells (MSCs) from the bone marrow of wild type and CD13KO mice
Immunofluorescent staining for the pluripotency marker Oct4 verified the multipotent potential of both wild type and CD13KO MSCs (Figure 1E)
Summary
Stem cells have the amazing capacity to contribute to the growth and healing of many different types of tissues and hold tremendous promise as therapeutic tools in many diseases. Mesenchymal stem cells (MSC) are a potential source of stem cells that have been shown to be effective in a range of cellular therapies in tissue engineering and regenerative medicine, but the biologic mechanisms underlying their function are just being elucidated. This knowledge is clearly essential to improving and optimizing stem cell therapies going forward. While no single cell surface marker unequivocally identifies MSCs from all tissues, consensus in the field has proposed three minimal criteria to distinguish MSCs from other hematopoietic stem cells (Dominici et al, 2006). Potential functional roles for CD13 in these cells have not been investigated
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