The Human Tissue–Biomaterial Interface: A Role for PPARγ-Dependent Glucocorticoid Receptor Activation in Regulating the CD163⁺M2 Macrophage Phenotype

Abstract

In vivo studies of implanted acellular biological scaffolds in experimental animals have shown constructive remodeling mediated by anti-inflammatory macrophages. Little is known about the human macrophage response to such biomaterials, or the nature of the signaling mechanisms that govern the macrophage phenotype in this environment. The cellular events at the interface of a tissue and implanted decellularized biomaterial were examined by establishing a novel ex vivo tissue culture model in which surgically excised human urinary tract tissue was combined with porcine acellular bladder matrix (PABM). Evaluation of the tissue-biomaterial interface showed a time-dependent infiltration of the biomaterial by CD68(+) CD80(-) macrophages. The migration of CD68(+) cells from the tissue to the interface was accompanied by maturation to a CD163(hi) phenotype, suggesting that factor(s) associated with the biomaterial or the wound edge was/were responsible for the active recruitment and polarization of local macrophages. Glucocorticoid receptor (GR) and peroxisome proliferator activated receptor gamma (PPARγ) signaling was investigated as candidate pathways for integrating inflammatory responses; both showed intense nuclear labeling in interface macrophages. GR and PPARγ activation polarized peripheral blood-derived macrophages from a default M1 (CD80(+)) toward an M2 (CD163(+)) phenotype, but PPARγ signaling predominated, as its antagonism blocked any GR-mediated effect. Seeding on PABM was effective at polarizing peripheral blood-derived macrophages from a default CD80(+) phenotype on glass to a CD80(-) phenotype, with intense nuclear localization of PPARγ. These results endorse in vivo observations that the infiltration of decellularized biological scaffolds, exemplified here by PABM, is pioneered by macrophages. Thus, it appears that natural factors present in PABM are involved in the active recruitment and polarization of macrophages to a CD163(+) phenotype, with activation of PPARγ identified as the candidate pathway. The harnessing of these natural matrix-associated factors may be useful in enhancing the integration of synthetic and other natural biomaterials by polarizing macrophage activation toward an M2 regulatory phenotype.

The effects of irradiation on the biological and biomechanical properties of an acellular porcine superflexor tendon graft for cruciate ligament repair

“…We have developed processes for the production of tissue specific biological scaffolds which preserve the physical properties, thus delivering multiscale hierarchical matrix architectures that replicate tissue‐specific biomechanical and biological functions. The process uses low concentration sodium dodecyl sulphate (SDS) and proteinase inhibitors and has been successfully applied to cardiovascular tissues, musculoskeletal tissues, and dermis, with evidence of the mechanisms of action and clinical utility of this approach now emerging . The process has been adopted to the development of a decellularized porcine superflexor tendon (pSFT) .…”

Naturally derived biomaterials for addressing inflammation in tissue regeneration

“…63 There, macrophages were the first cells to move from the tissue into the decellularized matrix, where they matured to CD163 + (M2 phenotype) cells. 63 …”

The Host Immune Response to Tissue-Engineered Organs: Current Problems and Future Directions

“…PPARγ signalling predominated in the polarization of macrophages from M1 (CD80+) towards M2 (CD163+) [105]. One of the problems with the use of a porcine model is that there is a dearth of markers for porcine cells.…”