Courtney Beard

Introduction:  Use of stem cells to repair or regenerate orthopedic tissue recently has become an area of intense research due to the high prevalence of tissue defects and injury. While bone tissue has been shown to be an extremely capable tissue when it comes to regeneration, large bony defect repair continues to be a challenge for orthopedic surgeons¹. Mesenchymal stem cells (MSCs) are the prevailing cells for orthopedic tissue engineering as they can differentiate into the bone, fat, cartilage, tendon, and muscle². Creating a strongly osteogenic micro-niche, is required to induce osteogenesis, which is achieved through cytokine signaling and macrophage switching³. Methods: The authors utilized bone marrow derived mesenchymal stem cells that were seeded onto bioceramic scaffolds. MSCs were cultured in IL-1 to mimic inflammatory conditions. The scaffolds were subcutaneously implanted into MHC H2b haplotype mice. Peripheral blood samples and explanted scaffolds were analyzed using antibodies, cell isolation, flow cytometry, Western blot, and sequence analysis. Chimeric mice received transplanted scaffolds to measure endothelial and osteogenic progenitor recruitment. Results: Macrophages infiltrated both types of scaffolds, but M2 macrophages were significantly more expressed in MSC-seeded scaffolds while M1 macrophages were increased in empty scaffolds⁴. IL1 induced MSCS to express COX-2 and other acute phase proteins. PGE₂ production and secretion was increased in the MSCs in response to IL-1 treatment and consequent NK-kB activation, triggering the functional switch from pro-inflammatory M1 macrophages to anti-inflammatory M2 phenotype⁴. BM-derived endothelial progenitor cells were mobilized by MSCs seeded onto the scaffolds, enhancing vasculogenesis of the tissue⁵. Bone marrow-derived CD146+CD105+ (osteogenic) cells were recruited into the bone regenerative niche created by the MSC scaffolds. 60 days after transplantation of the scaffolds, the transplants revealed the presence of bone forming with the scaffolds; bone tissue was of donor origin⁴.  Conclusions: Studies have shown that mesenchymal stem cells contribute to a favorable niche for osteogenesis through a cytokine cascade that ultimately induces phenotypic switching of macrophages to pro-resolving phenotype and recruitment of endothelial and osteogenic progenitor cells to enhance vasculogenesis and bone formation. A “wound signature” induced in the MSCs during an inflammatory environment is critical for this recruitment of endogenous cells and consequential regenerative processes⁶. This osteogenic niche created in the presence of MSCs may represent a new strategy for bony tissue repair.

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