Macrophagic response to human mesenchymal stem cell and poly(ϵ‐caprolactone) implantation in nonobese diabetic/severe combined immunodeficient mice

Abstract

Nonobese diabetic, severe combined immunodeficient (NOD/SCID) mice are extensively used to assess in vivo potentials for human cellular differentiation, development, and neophysiology. They are not only deficient in T and B cells, but also exhibit macrophage dysfunction and an absence of circulating complement. However, the survival of engrafted human mesenchymal stem cells (hMSCs) is limited and minimal mature bone tissue develops from implanted hMSCs in this model. The aim of the present study was to investigate the response to such implants in NOD/SCID mice. To this end, hMSCs genetically marked with enhanced green fluorescent protein, a biodegradable polymer, poly(ϵ-caprolactone) (PCL), and a bioconstruct incorporating the enhanced green fluorescent protein-labeled hMSCs with PCL after culture together for 3 weeks in vitro, were implanted into NOD/SCID mice and followed for up to 10 weeks. Monocytes/macrophages appeared to be the major invading cell type in all the implants and remained in the materials regardless of whether or not hMSCs were present over the time periods studied. When the hMSCs were implanted without the PCL scaffold, host macrophage invasion was also observed with the majority of hMSCs being eliminated within 2 weeks. Multinuclear giant cells or foreign body giant cells were seen in the cases of PCL implantation. These cells slowly infiltrated into the central core of the materials over a 10-week period of implantation with neutrophils and mast cells also being observed. In conclusion, in NOD/SCID mice, monocytes/macrophages still effectively respond to the implantation of xenografts and biopolymers with functional migration, phagocytosis, adhesion, foreign body recognition and formation of multinuclear giant cells, or foreign body giant cells. Thus, these animals still retain a level of innate immune responsiveness to these implantations and in addition may provoke a physiological environment that is unsuitable for extensive intramembranous ossification by engrafted hMSCs. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 71A: 538–548, 2004